Quinoline Quest: Kynurenic Acid Strategies for Next-Generation Therapeutics via Rational Drug Design

1. Introduction

Tryptophan (Trp) undergoes a fascinating series of biochemical transformations through kynurenine (KYN) metabolism that leads to the production of various neuroactive and immunomodulatory compounds [1]. At the heart of this metabolic arm lies a cascade of enzymes that generates an array of quinoline-based molecules, each with distinct and sometimes opposing effects on cellular and molecular processes [2]. Among the most scrutinized products are kynurenic acid (KYNA) and quinolinic acid (QUIN), which play critical roles in modulating neurotransmission, safeguarding neurons, and orchestrating immune responses [3]. Under normal circumstances, these molecules contribute to the finely tuned balance between protection and subtle regulation of neural function [4]. However, an overabundance or misregulation of these compounds can fuel diverse pathologies, spanning neurodegenerative conditions, psychiatric disorders, and even certain cancers [5]. It is remarkable that these metabolites, found in species across the evolutionary spectrum, have retained their functional importance over millions of years [6]. Their enduring presence suggests a fundamental role in maintaining physiological homeostasis, yet they can also become potent drivers of disease when their levels shift [7]. This duality underscores the importance of understanding both the biochemical nuances and the broader biological contexts in which these quinoline-based substances operate [3,8].

Figure 1. The structure of quinoline. The quinoline scaffold, featuring a fused benzene and pyridine ring, forms the structural backbone of many biologically active compounds.

Figure 1. The structure of quinoline. The quinoline scaffold, featuring a fused benzene and pyridine ring, forms the structural backbone of many biologically active compounds.

The quinoline skeleton lies at the heart of a wide variety of biologically active molecules, encompassing endogenous metabolites such as KYNA and QUIN, as well as numerous synthetic derivatives found in pharmaceuticals and research tools [9]. Defined by a fused ring structure that merges a benzene ring with a pyridine ring, quinoline offers countless opportunities for chemical substitution [10]. Small modifications, like adding carboxyl or hydroxyl groups, can dramatically alter a molecule’s behavior, influencing everything from its solubility and stability to its affinity for specific protein targets [11]. Halogenation, for instance, may boost lipophilicity and enhance central nervous system penetration, while the presence or absence of an acidic group can shape receptor-binding preferences [12]. In many cases, these structural nuances determine whether a particular quinoline derivative acts as a neuroprotective agent or exacerbates excitotoxic processes through receptors like N-methyl-D-aspartate (NMDA) or G protein-coupled receptor 35 (GPR35) [13]. Endogenous metabolites derived from the Trp degradation route typically exhibit distinct features that help them coordinate intricate cellular signaling, whereas synthetic derivatives, exemplified by quinolone antibiotics, have been optimized for pathogen clearance and bioavailability [14]. Despite their diverse origins, all members of this chemical family share the versatile quinoline core, highlighting the importance of structural considerations in developing targeted interventions for various clinical needs [15].

A hallmark of these Trp-derived quinoline compounds is their profound influence on the delicate balance between neuroprotection and neurotoxicity [16]. Their functions are finely tuned by their relative concentrations, contextual factors, and micro-environment, shaping their cumulative effects [17]. Beyond their influence in the central nervous system, these metabolites also bridge metabolic and immune pathways, as illustrated by enzymes like indoleamine 2,3-dioxygenases (IDOs) and tryptophan 2,3-dioxygenase (TDO) [18]. When activity in this biochemical system goes awry, it can fuel inflammation and shape disease trajectories in conditions as diverse as autoimmunity and cancer [19]. Emerging evidence further suggests crosstalk with the aryl hydrocarbon receptor, hinting at broader physiological roles that extend beyond neuronal circuits [20]. Such multifaceted involvement underscores the need to appreciate how these molecules orchestrate, or disrupt, redox equilibrium, synaptic communication, and immune surveillance in tandem [21]. By simultaneously affecting protective and damaging processes, they embody a paradox: slight imbalances may tip the scale toward pathology [22,23]. Investigating this interplay is vital for deciphering the biology behind complex disorders, as well as for pinpointing novel therapeutic entry points grounded in the chemistry of quinoline-based metabolites.

Therapeutic strategies centered on Trp metabolism have garnered considerable attention in recent years, buoyed by encouraging preclinical results and a surge in clinical trials [24,25]. For instance, inhibitors of IDOs showed early promise in oncology by dampening immunosuppressive pathways and restoring anti-tumor responses [26]. However, some late-stage trials yielded disappointingly modest outcomes, illustrating the complexity of translating metabolic interventions into measurable clinical benefits [27]. Another avenue involves exploiting analogs of KYNA, such as 7-CKA, which demonstrates potential for alleviating schizophrenia-related symptoms by modulating glutamate receptors [28]. While these developments highlight the promise of quinoline-based therapeutics, numerous challenges remain [29]. Achieving adequate penetration across the blood-brain barrier (BBB) can be particularly daunting, as can mitigating off-target effects that may compromise patient safety [30]. Beyond endogenously derived agents, certain quinoline derivatives traditionally used for other indications such as quinine and related molecule, are now being explored for their neuroprotective or anti-inflammatory properties [31]. Repurposing these compounds offers the opportunity to fast-track clinical testing, taking advantage of existing safety and pharmacokinetic data [32]. Yet, optimizing dosage, delivery methods, and specificity remains a priority [33]. Moving forward, interdisciplinary collaborations will likely prove vital, melding synthetic chemistry, pharmacology, and clinical expertise to refine these agents and harness their untapped therapeutic potential [34].

Despite the steady growth of research into quinoline-containing molecules, there are still pressing questions that need answers [35]. One pivotal gap lies in our limited understanding of how specific structural modifications translate into particular biological effects, often termed structure-activity relationships [36]. Such insights are crucial for guiding rational drug design and for predicting how a new derivative might behave in living systems. Another hurdle is the fragmented nature of pharmacokinetic and safety data, which often emerge from small, isolated studies rather than comprehensive analyses [37]. This piecemeal approach complicates efforts to compare efficacy and toxicity across different quinoline scaffolds [37]. Furthermore, there is a noticeable lack of head-to-head evaluations between endogenous Trp-derived metabolites and synthetic or exogenous analogs, preventing a clear assessment of relative benefits and risks. Building on these concerns, the objectives of this review are threefold. First, to systematically evaluate the wealth of endogenous and synthetic quinoline-based compounds for their therapeutic potential in various disease contexts. Second, to synthesize current knowledge about structure-activity relationships with the explicit goal of identifying a candidate inspired by KYNA that might serve as a leading drug template. Lastly, we aim to propose innovative strategies to address translational challenges, including targeted prodrug design and approaches that can engage multiple biological targets simultaneously.

2. Unveiling Endogenous Quinolines in the Kynurenine (KYN) Pathway: A Gateway to Kynurenic Acid (KYNA)–Driven Neuroprotection and Rational Drug Design

The metabolism of Trp produces a striking array of bioactive compounds [38]. KYNA, QUIN, nicotinic acid (NA), picolinic acid, xanthurenic acid (XA), and quinaldic acid each exert profound effects on human physiology [39]. Current research suggests these metabolites act as fragile regulators, holding the potential to tip the balance between neuroprotection and neurotoxicity [40]. KYNA, often described as a safeguard against excitotoxicity, dampens glutamatergic signaling [41]. In contrast, QUIN can escalate excitatory activity to dangerous extremes, contributing to neuronal injury under pathological conditions [42]. NA supports redox homeostasis, while picolinic acid and XA coordinate metal ions, subtly influencing cellular stability [43]. Quinaldic acid remains a shadowed figure in this biochemical network, its roles only beginning to emerge. These metabolites do not function in isolation. They respond to the surrounding microenvironment and reshape it in ways that may ultimately define the trajectory of health and disease (Table 1).

2.1. Structural & Functional Synergy

The quinoline core appears in a range of Trp-derived metabolites, revealing an intriguing contrast in their biological effects [2]. KYNA and QUIN emerge from the same metabolic pathway, yet they are traditionally considered to operate on opposite ends of the spectrum [68]. One protects neurons by dampening excessive excitatory signaling; the other drives excitotoxic damage often linked to inflammation [89]. This shared structural backbone, paired with such starkly different outcomes, suggests a delicate evolutionary balance shaped by minor molecular adjustments [2]. Consider how slight modifications to substituent groups on the quinoline ring can shift a molecule’s interaction with receptors, ion channels, or transporters [90]. Even fluctuations in pH or enzyme activity are enough to sway the system toward protection or harm [91]. There’s more: metal ions and cofactors add another layer of control, either amplifying or suppressing activity [92]. The challenge now lies in identifying how to steer this balance [93]. Could targeted changes to the quinoline scaffold enhance KYNA’s protective roles or curb the destructive potential of QUIN? [94] Understanding these subtle structural cues opens the door to designing molecules with more favorable effects on neural health.

Small structural modifications within quinoline-based metabolites can significantly influence their biological activity and stability [95]. Altering the position of a hydroxyl group, as observed in XA, affects hydrogen bonding capacity and lipophilicity, which may shift receptor affinity and metabolic processing [96]. These effects are particularly relevant when examining interactions with glutamate receptors such as NMDA, where even minor variations can determine whether a metabolite contributes to neuroprotection or excitotoxicity [97]. Similar patterns emerge with GPR35, a receptor that responds differently based on the specific substituents attached to the quinoline scaffold [98]. Variations in these groups regulate receptor engagement and downstream signaling pathways, shaping distinct physiological outcomes [91]. Alongside receptor interactions, metabolic stability is also sensitive to changes in ionization states and enzyme susceptibility, both of which are closely tied to the positioning of carboxyl, hydroxyl, or amino groups [99]. Mapping these structural features across endogenous metabolites provides insights into how they influence pathological processes [100,101]. Examining the relationship between substitution patterns, receptor selectivity, and metabolic half-life may contribute to the design of compounds that adjust the activity of quinoline derivatives in targeted therapeutic contexts.

2.2. Key Gaps in Translation

Despite their diverse biological activities, translating endogenous quinoline-based compounds into therapeutic interventions faces significant hurdles [102]. A chief concern is poor bioavailability, particularly evident in KYNA [103]. Its polar carboxylate group hinders passive diffusion across biological membranes and limits the ability to reach target sites in sufficient concentration [104]. On the other hand, picolinic acid, while exhibiting promising immunomodulatory and metal-chelating activities, undergoes rapid metabolism, leading to short half-life and unstable plasma levels [105]. These kinetic and physicochemical drawbacks are further complicated by the complexity of enzymatic pathways involved, where small fluctuations in metabolic rates can greatly alter the overall balance of protective versus pathogenic metabolites [106]. Such pharmacokinetic challenges underscore the difficulty of achieving consistent dosing in clinical settings [107]. As highlighted in recent efforts to refine KYN system monitoring, relying solely on static concentrations or simplistic ratios may be insufficient. A more nuanced, integrative biomarker framework is needed to capture the dynamic regulation of tryptophan metabolism and guide precision medicine applications in neuropsychiatric and neurodegenerative disorders [108]. Moreover, existing animal models do not always recapitulate human physiology, complicating the interpretation of efficacy and toxicity data [55]. Without efficient strategies to enhance bioavailability—such as prodrug approaches, targeted delivery systems, or structural modifications to increase lipophilicity—these compounds may struggle to meet clinical requirements [109]. As research deepens our understanding of how structural and functional attributes influence pharmacokinetics, efforts to overcome these limitations can be directed more precisely, potentially unlocking the therapeutic promise that many of these metabolites have long suggested.

Translating endogenous quinoline compounds into real-world treatments often involves navigating paradoxical biological roles, as exemplified by NA [110,111]. Widely recognized for its capacity to modulate lipid metabolism and improve cardiovascular profiles, NA also harbors less appreciated functions in inflammatory pathways [112]. This duality creates both opportunity and challenge: on one hand, its impact on lipid-lowering has made it a mainstay in certain therapeutic regimens; on the other hand, emerging studies suggest that NA can engage molecular cascades involved in neuroinflammation, potentially influencing conditions like neurodegenerative diseases [113,114]. Such conflicting actions underscore a larger theme in quinoline-related research, where a single molecule may oscillate between protective and pathogenic effects depending on context and concentration [115]. The incomplete mapping of these dual functionalities hampers our ability to refine dosing strategies or identify the specific patient populations who might benefit the most [91]. Additionally, the diverse array of downstream metabolites and receptors further complicates the picture, making it difficult to anticipate long-term outcomes [116]. As a result, bridging the gap from bench to bedside requires a thorough understanding of how NA’s manifold roles intersect. Only by disentangling these intricate mechanisms can researchers devise targeted interventions that harness the therapeutic benefits of NA while minimizing unanticipated consequences.

A major obstacle in harnessing the therapeutic potential of endogenous quinoline compounds lies in their limited tissue penetration and rapid clearance [49]. KYNA, for example, is known to possess neuroprotective properties but struggles to traverse biological barriers effectively, largely due to its polar carboxyl group [103]. One promising strategy is to employ prodrug approaches such as 4-chlorokynurenine and SZR-104, whereby this polar moiety is temporarily masked through esterification or similar chemical modifications [49,117]. By doing so, researchers can enhance lipophilicity, potentially improving permeability across the gut or BBB. Once inside target tissues, endogenous enzymes would cleave the ester bond, liberating active KYNA precisely where it is needed [118]. Another avenue involves synthesizing hybrid molecules, combining the core quinoline structure with lipid-soluble components [119]. This approach aims not only to improve membrane permeability but also to confer additional functional advantages, such as greater stability or targeted delivery [120]. For instance, merging KYNA with a fatty acid chain could optimize drug distribution in neuronal membranes, where excitotoxic processes frequently unfold [62]. While these strategies are conceptually appealing, they require systematic evaluation to ensure that altered pharmacokinetics do not come at the cost of diminished efficacy or unexpected side effects. Nevertheless, such chemical innovations hold great promise for translating endogenous metabolites into clinically viable treatments.

One approach to bridging the gap between preclinical promise and clinical success lies in developing dual-targeting compounds that can simultaneously influence key enzymes in Trp metabolism and modulate neuroinflammatory pathways [121]. By tackling both processes at once, these agents have the potential to dampen the production of harmful quinoline-based metabolites, such as QUIN, while also curbing inflammatory cascades that can exacerbate neuronal damage [122]. For instance, selective inhibition of enzymes like IDOs or TDO could be paired with suppression of pro-inflammatory cytokines, ultimately reducing excitotoxic insults in conditions such as neurodegeneration or chronic inflammation [123,124,125]. n diseases like multiple sclerosis, recent work emphasizes the critical importance of accurately monitoring redox dynamics as both a diagnostic tool and a therapeutic target, revealing that oxidative imbalance directly influences disease progression and treatment responsiveness [126]. The rationale is to address multiple disease mechanisms in parallel, thereby enhancing therapeutic efficacy and possibly reducing the likelihood of resistance or relapse [127]. However, designing these dual-acting agents demands a nuanced understanding of each target’s regulatory networks, as altering enzyme activity may unintentionally shift the balance toward alternative metabolic routes or trigger compensatory immune responses [128]. Moreover, the BBB remains a formidable challenge, necessitating delivery strategies that ensure sufficient drug concentrations within the central nervous system [129]. Despite these hurdles, dual-targeting compounds offer a forward-thinking strategy, uniting key biochemical nodes into a single intervention that could revolutionize how we harness endogenous quinoline metabolites for clinical benefit.

3. Expanding the Quinoline Landscape: Derivatives Beyond the Kynurenine (KYN) Metabolic Pathway

Emerging evidence supports the repurposing of established pharmacophores with known activities—such as quinine’s antimalarial and 8-hydroxyquinoline’s metal-chelating properties—to modulate the kynurenine pathway through mechanisms like IDO inhibition and redox modulation [130]. However, these compounds may present limitations, including off-target bacterial DNA gyrase inhibition (e.g., nalidixic acid) or toxicity concerns (cinchoninic acid derivatives) [131,132]. Structural homology between isonicotinic acid (INA)’s pyridine ring and KYNA’s quinoline core highlights opportunities for scaffold hybridization and the exploration of underexamined agents, like dipicolinic acid (DPA), in neurodegeneration. Further, systematic SAR studies on broad-spectrum drugs, exemplified by quinidine, could isolate neuroactive fragments for targeted therapeutic applications and ultimately safer use [133].

Table 2. Structural and pharmacological overview of quinoline, quinolone derivatives, and pyridinecarboxylic acids. Key compounds within these chemical classes are categorized alongside their main therapeutic actions, biological targets, and significant applications. This table traces the progression from classic antimalarials to contemporary antibiotics, emphasizing how structural changes shape efficacy, safety profiles, and clinical relevance.

Compounds	Main characteristics	Ref.
Quinoline and quinolone derivatives
Quinine Quinidine	Quinine: Antimalarial agent – Inhibits Plasmodium pp. by interfering with heme detoxification Historically used to reduce fever and pain Muscle relaxant – Helps alleviate nocturnal leg cramps by modulating ion channels Quinidine: Class I antiarrhythmic – Blocks sodium channels, stabilizing cardiac rhythm Chiral isomer of quinine – Shares structural similarities but has distinct pharmacological effects Proarrhythmic risk – Can prolong QT interval 1, requiring careful clinical use	[134,135,136] [137,138,139] [140,141] [142,143,144] [145,146,147] [148,149,150]
Cinchoninic Acid	Quinoline derivative – Structurally related to quinine and other cinchona alkaloids Metal chelation – Binds with metal ions, potentially influencing enzymatic activity Pharmacological potential – Investigated for antimicrobial and neuroactive properties	[141,151,152] [153,154] [155,156,157]
2-Quinolinone 4-Quinolinone	Core scaffold for quinolone antibiotics – Forms the backbone of fluoroquinolones, targeting bacterial DNA gyrase and topoisomerase IV Broad-spectrum antimicrobial Activity – Effective against Gram-positive and Gram-negative bacteria Synthetic Versatility – Modifiable structure allows for improved potency, pharmacokinetics, and resistance mitigation.	[158,159,160] [161,162,163] [162,164,165]
Nalidixic Acid	First-generation quinolone antibiotic – Inhibits DNA gyrase, primarily effective against Gram-negative bacteria Limited spectrum & rapid resistance – Narrow activity and high bacterial resistance limit its clinical use Urinary tract infection treatment – Historically used for urinary tract infections, though largely replaced by newer fluoroquinolones	[166,167,168] [169,170] [171,172,173]
Oxolinic Acid	Early quinolone antibiotic – Inhibits DNA gyrase, effective against Gram-negative bacteria Used in veterinary medicine – Primarily employed for treating bacterial infections in animals Limited clinical use – Replaced by newer fluoroquinolones due to resistance and pharmacokinetic limitations	[174,175,176] [177,178,179] [180]
Pyridinecarboxylic Acids
Isonicotinic Acid (INA)	Pyridine carboxylic acid derivative – Structurally related to NA (vitamin B3). Key precursor for isoniazid – Used in the synthesis of isoniazid, a frontline anti-tuberculosis drug. Pharmacological Potential – Investigated for antimicrobial and metabolic regulatory properties	[181,182] [183,184] [183,185,186]
Dipicolinic Acid (DPA)	Metal ion chelator – Strongly binds calcium and other metal ions, playing a role in metal homeostasis Bacterial spore component – Essential for bacterial endospore resistance and heat stability Potential neuroprotective role – Explored for its effects on metal-related oxidative stress in neurodegeneration	[187,188] [189] [190,191,192]
Hydroxy-Substituted Derivatives
8-Hydroxyquinoline	Metal clator – Strongly binds iron, copper, and zinc, influencing redox balance and enzymatic activity Antimicrobial and antifungal agent – Exhibits broad-spectrum activity against bacteria and fungi Potential neuroprotective role – Investigated for treating neurodegenerative diseases by regulating metal toxicity	[193,194,195] [196,197,198] [199,200,201]

¹ QT interval, Time between onset of Q wave and end of T wave on electrocardiogram (ECG), reflecting ventricular depolarization and repolarization. NA, nicotinic acid.

Table 2. Structural and pharmacological overview of quinoline, quinolone derivatives, and pyridinecarboxylic acids. Key compounds within these chemical classes are categorized alongside their main therapeutic actions, biological targets, and significant applications. This table traces the progression from classic antimalarials to contemporary antibiotics, emphasizing how structural changes shape efficacy, safety profiles, and clinical relevance.

Compounds	Main characteristics	Ref.
Quinoline and quinolone derivatives
Quinine Quinidine	Quinine: Antimalarial agent – Inhibits Plasmodium pp. by interfering with heme detoxification Historically used to reduce fever and pain Muscle relaxant – Helps alleviate nocturnal leg cramps by modulating ion channels Quinidine: Class I antiarrhythmic – Blocks sodium channels, stabilizing cardiac rhythm Chiral isomer of quinine – Shares structural similarities but has distinct pharmacological effects Proarrhythmic risk – Can prolong QT interval 1, requiring careful clinical use	[134,135,136] [137,138,139] [140,141] [142,143,144] [145,146,147] [148,149,150]
Cinchoninic Acid	Quinoline derivative – Structurally related to quinine and other cinchona alkaloids Metal chelation – Binds with metal ions, potentially influencing enzymatic activity Pharmacological potential – Investigated for antimicrobial and neuroactive properties	[141,151,152] [153,154] [155,156,157]
2-Quinolinone 4-Quinolinone	Core scaffold for quinolone antibiotics – Forms the backbone of fluoroquinolones, targeting bacterial DNA gyrase and topoisomerase IV Broad-spectrum antimicrobial Activity – Effective against Gram-positive and Gram-negative bacteria Synthetic Versatility – Modifiable structure allows for improved potency, pharmacokinetics, and resistance mitigation.	[158,159,160] [161,162,163] [162,164,165]
Nalidixic Acid	First-generation quinolone antibiotic – Inhibits DNA gyrase, primarily effective against Gram-negative bacteria Limited spectrum & rapid resistance – Narrow activity and high bacterial resistance limit its clinical use Urinary tract infection treatment – Historically used for urinary tract infections, though largely replaced by newer fluoroquinolones	[166,167,168] [169,170] [171,172,173]
Oxolinic Acid	Early quinolone antibiotic – Inhibits DNA gyrase, effective against Gram-negative bacteria Used in veterinary medicine – Primarily employed for treating bacterial infections in animals Limited clinical use – Replaced by newer fluoroquinolones due to resistance and pharmacokinetic limitations	[174,175,176] [177,178,179] [180]
Pyridinecarboxylic Acids
Isonicotinic Acid (INA)	Pyridine carboxylic acid derivative – Structurally related to NA (vitamin B3). Key precursor for isoniazid – Used in the synthesis of isoniazid, a frontline anti-tuberculosis drug. Pharmacological Potential – Investigated for antimicrobial and metabolic regulatory properties	[181,182] [183,184] [183,185,186]
Dipicolinic Acid (DPA)	Metal ion chelator – Strongly binds calcium and other metal ions, playing a role in metal homeostasis Bacterial spore component – Essential for bacterial endospore resistance and heat stability Potential neuroprotective role – Explored for its effects on metal-related oxidative stress in neurodegeneration	[187,188] [189] [190,191,192]
Hydroxy-Substituted Derivatives
8-Hydroxyquinoline	Metal clator – Strongly binds iron, copper, and zinc, influencing redox balance and enzymatic activity Antimicrobial and antifungal agent – Exhibits broad-spectrum activity against bacteria and fungi Potential neuroprotective role – Investigated for treating neurodegenerative diseases by regulating metal toxicity	[193,194,195] [196,197,198] [199,200,201]

¹ QT interval, Time between onset of Q wave and end of T wave on electrocardiogram (ECG), reflecting ventricular depolarization and repolarization. NA, nicotinic acid.

3.1. Repurposing Potential

XA, although not a central intermediate in the KYN pathway, illustrates how precise structural changes can influence receptor interactions and metabolic stability [202]. Introducing a hydroxyl group at specific sites on the quinoline ring modifies hydrogen bonding capacity, which may shift affinity toward NMDA receptors or GPR35 [98]. Such alterations affect not only receptor binding but also downstream processes, including neurotransmission and immune signaling [203]. Adjustments in stereochemistry or the addition of other substituents can further redirect molecular preferences, raising the possibility of selectively targeting distinct physiological pathways [204]. Yet, enhancing receptor specificity often comes with trade-offs [205]. For instance, while certain hydroxylations strengthen binding, they may also increase vulnerability to enzymatic degradation [206]. Strategies such as incorporating protective groups or additional ring modifications can help extend plasma half-life and improve pharmacokinetic profiles [207]. Beyond structural design, patient stratification based on genetic variations in enzymes like IDOs and KMO offers a route to refine therapeutic applications [208]. Identifying metabolic subgroups may improve treatment outcomes and reduce adverse effects, particularly in neurodegenerative and neuroinflammatory conditions, where individual responses vary widely [209].

Quinoline derivatives beyond the KYN pathway present structural opportunities but are often limited by safety concerns that complicate therapeutic development [102]. Nalidixic acid, widely recognized for its antibacterial activity through inhibition of DNA gyrase, raises concerns when considered for neuroprotective or immunomodulatory purposes [210]. Interference with DNA metabolism, while effective against bacterial targets, may introduce risks to human cells, particularly in long-term or systemic applications [211]. Similar challenges appear with cinchoninic acid derivatives, which share structural features with KYNs yet exhibit toxicity that restricts clinical use [212]. In several cases, these effects appear linked to the formation of reactive metabolites or unintended interactions with metabolic enzymes [213]. Even minor modifications to the quinoline scaffold can redirect metabolic pathways, sometimes amplifying toxic outcomes [214]. Addressing these complexities requires a detailed understanding of structure-toxicity relationships and strategies that preserve pharmacological activity while minimizing off-target effects [215]. Approaches such as selective functional group modifications and alternative synthetic routes are under investigation [216]. Advancing these efforts depends on collaboration across medicinal chemistry, toxicology, and clinical research to reduce liabilities and support the development of safer quinoline-based compounds [217].

3.2. Bridging to Kynurenic acid (KYNA)-Based Targets

Structural similarities between INA and KYNA have prompted interest in hybrid molecules that combine elements of both frameworks [218]. Each features a nitrogen-containing heterocycle capable of influencing receptor interactions and electron distribution [219]. By integrating portions of the quinoline core from KYNA with the pyridine ring of INA, researchers aim to enhance selectivity at targets such as NMDA receptors and GPR35. This approach allows for adjustments in ring orientation and substituent placement, offering opportunities to fine-tune receptor engagement while addressing challenges related to metabolic stability [220]. The isonicotinic scaffold, in particular, provides flexibility for introducing functional groups that may improve solubility or permeability [221]. While these modifications hold promise for minimizing off-target effects, the relationship between structural changes and pharmacological outcomes remains complex [222]. Balancing synthetic accessibility with therapeutic potential requires careful evaluation of how hybrid designs alter binding properties and metabolic pathways. Drawing from existing knowledge of INA derivatives, ongoing studies will assess whether these structural combinations can deliver improved performance while limiting adverse effects, especially in applications involving neuroprotective and immunomodulatory pathways.

DPA, a pyridine-2,6-dicarboxylic acid, remains relatively underexplored despite its capacity to bind metal ions commonly implicated in neurodegenerative diseases [223]. Through interactions with iron, zinc, and copper, DPA may contribute to regulating metal balance, a process closely linked to oxidative stress and protein aggregation [224]. Preliminary findings suggest potential roles in modulating inflammatory responses and excitatory signaling, raising questions about its relevance to therapeutic strategies aimed at neuroprotection [225]. Structurally, the resemblance between DPA's pyridine core and the quinoline ring of KYNA presents opportunities to combine metal-chelation with receptor targeting [226]. This dual functionality may prove valuable, particularly in disorders where oxidative damage and glutamatergic dysregulation intersect [227]. Parkinson’s disease and Alzheimer’s disease are two examples where such mechanisms converge, though much remains unknown regarding DPA's pharmacological behavior [228]. Determining its metabolic stability, toxicity profile, and specific enzyme interactions will be essential for guiding further development [229]. By applying knowledge from KYNA analog research, it may be possible to design compounds that extend the benefits of metal-binding while refining receptor selectivity, supporting efforts to address complex neurodegenerative conditions [230].

3.3. Innovative Directions

Identifying neuroactive components within broad-spectrum quinoline derivatives offers a pathway to develop treatments with fewer adverse effects [12]. Quinidine, primarily recognized for its role in modulating cardiac ion channels, provides a useful example [217]. Through structure-activity relationships analysis, specific molecular features can be mapped to isolate those contributing to neurological benefits, such as limiting excitotoxicity, while reducing the risk of arrhythmias [231,232]. Computational docking and high-throughput screening techniques assist in pinpointing functional groups that influence ion channels within the central nervous system, rather than the heart [233]. These insights guide the design of analogues tailored to interact with neuronal targets, including channels and receptors implicated in neurodegenerative disorders [234]. Achieving this balance between therapeutic effect and safety often relies on incremental structural adjustments—altering side chains, introducing new substituents, or modifying ring systems can significantly affect binding behavior and metabolic stability [235]. While quinidine’s properties are well characterized, questions remain about how best to adapt its framework for neurological applications [236]. Ongoing work with related compounds may help define strategies to refine multi-purpose quinoline scaffolds and explore their potential in treating conditions such as epilepsy, chronic pain, and neurodegeneration.

4. Exogenous Horizons: Synthetic Quinoline Scaffolds in Rational Drug Design

Driven by rational design approaches, synthetic modifications to quinoline-based scaffolds have enhanced both target engagement and pharmacokinetic profiles [237]. For example, chlorination in 7-CKA and sulfonamide substitution in Gavestinel improved NMDA receptor blockade and bioavailability, respectively [238,239,240,241]. Despite promising preclinical data, clinical outcomes have not always matched expectations—Gavestinel, for instance, failed in stroke trials [242]. Encouragingly, newer therapies like laquinimod show immunomodulatory benefits in multiple sclerosis [243]. These developments highlight the challenge of balancing selectivity and polypharmacology, exemplified by L-701,324’s potent NMDA antagonism and glutamatergic side effects [244]. Future strategies emphasize BBB-penetrant analogs and multi-target ligands exemplified by tasquinimod, including HDAC (histone deacetylase) 4 inhibition and aryl hydrocarbon receptor modulation.

Table 3. Synthetic exogenous quinoline-based compounds: structures and pharmacological profiles. Synthetic and exogenous quinoline derivatives are outlined here, with emphasis on their primary mechanisms of action, therapeutic potential, and development hurdles. Each compound is linked to its intended molecular target—from NMDA receptor antagonism to immunomodulatory and anticancer functions—and is accompanied by references for in-depth exploration.

	Compounds	Main characteristics	Ref.
	7-Chlorokynurenic Acid (7-CKA)	NMDA receptor antagonist – Blocks the glycine-binding site, reducing excitotoxicity. Preclinical behavioral actions – Elicits antidepressant-like effects, blocks NMDA-induced convulsions, and attenuates ischemia-induced learning deficits Clinical trials – 4-Clorokynurenin, a prodrug of 7-CKA show no significant antidepressant effects in treatment-resistant depression and launched a clinical trial for neuropathic pain	[245,246] [247,248,249] [250]
	5,7-Dichlorokynurenic Acid	NMDA receptor antagonist – Blocks the glycine site to reduce excitotoxicity Enhanced potency – More effective than KYNA at inhibiting NMDA receptor activity Preclinical behavioral actions – Show anxiolytic effects and enhance short-term memory and recognition	[251,252,253] [238,251,253,254] [255,256,257]
	L-701,324	NMDA receptor antagonist – Blocks the glycine site, reducing excitotoxicity Preclinical behavioral evidence – Demonstrates antidepressant-like activity, Reduce anxiety-like behavior Potential clinical application –Epilepsy, schizophrenia, and chronic pain	[258,259] [257,260] [261,262,263]
	Gavestinel	Glycine site NMDA receptor antagonist – Blocks NMDA receptor activity to reduce excitotoxicity Preclinical behavioral findings – potential in reducing ischemic damage and modulating certain NMDA receptor-mediated schizophrenia-like behaviors Stroke neuroprotection Candidate – Investigated for acute stroke, primary intracerebral hemorrhage, acute ischemic stroke, but failed in clinical trials.	[264,265] [264,266] [264,267,268]
	Laquinimod	Immunomodulatory agent – Reduces pro-inflammatory cytokines and modulates immune cell activity Preclinical findings – Improve motor function in a Huntington's disease model, activate the AhR in the EAE Model of MS Clinical trials – Modestly reduce relapse rates and disability progression and significantly reduce brain volume change atrophy in relapsing-remitting MS, and show limited efficacy in active non-infectious intermediate, posterior, or panuveitis (NCT02720102)	[269,270,271] [272,273] [274,275,276]
	Tasquinimod	Anti-cancer properties – Inhibits tumor angiogenesis, suppresses myeloid-derived suppressor cells, downregulate immune suppressive pathways and inflammatory cytokine signaling S100A9 modulation – Suppress inflammatory factor expression, potentially inhibit the upregulation of S100A9 in AD, and inhibit MDSC recruitment HDAC4 Modulation – potentially influence epigenetic regulation in neurodegenerative or cognitive disorders and potentially control neuronal memory, plasticity, and learning	[277,278,279] [280,281,282] [283,284]

AD, Alzheimer’s disease; HDAC, histone deacetylase; AhR, aryl hydrocarbon receptor; EAE, experimental autoimmune encephalomyelitis, MS: multiple sclerosis; MDSCs, myeloid-derived duppressor cells.

Table 3. Synthetic exogenous quinoline-based compounds: structures and pharmacological profiles. Synthetic and exogenous quinoline derivatives are outlined here, with emphasis on their primary mechanisms of action, therapeutic potential, and development hurdles. Each compound is linked to its intended molecular target—from NMDA receptor antagonism to immunomodulatory and anticancer functions—and is accompanied by references for in-depth exploration.

	Compounds	Main characteristics	Ref.
	7-Chlorokynurenic Acid (7-CKA)	NMDA receptor antagonist – Blocks the glycine-binding site, reducing excitotoxicity. Preclinical behavioral actions – Elicits antidepressant-like effects, blocks NMDA-induced convulsions, and attenuates ischemia-induced learning deficits Clinical trials – 4-Clorokynurenin, a prodrug of 7-CKA show no significant antidepressant effects in treatment-resistant depression and launched a clinical trial for neuropathic pain	[245,246] [247,248,249] [250]
	5,7-Dichlorokynurenic Acid	NMDA receptor antagonist – Blocks the glycine site to reduce excitotoxicity Enhanced potency – More effective than KYNA at inhibiting NMDA receptor activity Preclinical behavioral actions – Show anxiolytic effects and enhance short-term memory and recognition	[251,252,253] [238,251,253,254] [255,256,257]
	L-701,324	NMDA receptor antagonist – Blocks the glycine site, reducing excitotoxicity Preclinical behavioral evidence – Demonstrates antidepressant-like activity, Reduce anxiety-like behavior Potential clinical application –Epilepsy, schizophrenia, and chronic pain	[258,259] [257,260] [261,262,263]
	Gavestinel	Glycine site NMDA receptor antagonist – Blocks NMDA receptor activity to reduce excitotoxicity Preclinical behavioral findings – potential in reducing ischemic damage and modulating certain NMDA receptor-mediated schizophrenia-like behaviors Stroke neuroprotection Candidate – Investigated for acute stroke, primary intracerebral hemorrhage, acute ischemic stroke, but failed in clinical trials.	[264,265] [264,266] [264,267,268]
	Laquinimod	Immunomodulatory agent – Reduces pro-inflammatory cytokines and modulates immune cell activity Preclinical findings – Improve motor function in a Huntington's disease model, activate the AhR in the EAE Model of MS Clinical trials – Modestly reduce relapse rates and disability progression and significantly reduce brain volume change atrophy in relapsing-remitting MS, and show limited efficacy in active non-infectious intermediate, posterior, or panuveitis (NCT02720102)	[269,270,271] [272,273] [274,275,276]
	Tasquinimod	Anti-cancer properties – Inhibits tumor angiogenesis, suppresses myeloid-derived suppressor cells, downregulate immune suppressive pathways and inflammatory cytokine signaling S100A9 modulation – Suppress inflammatory factor expression, potentially inhibit the upregulation of S100A9 in AD, and inhibit MDSC recruitment HDAC4 Modulation – potentially influence epigenetic regulation in neurodegenerative or cognitive disorders and potentially control neuronal memory, plasticity, and learning	[277,278,279] [280,281,282] [283,284]

AD, Alzheimer’s disease; HDAC, histone deacetylase; AhR, aryl hydrocarbon receptor; EAE, experimental autoimmune encephalomyelitis, MS: multiple sclerosis; MDSCs, myeloid-derived duppressor cells.

4.1. Rational Design Successes and Failure

Refining quinoline scaffolds through targeted synthetic modifications has proven effective in improving receptor selectivity and pharmacokinetic properties [285]. In the case of 7-CKA, introducing a chlorine atom at the 7-position strengthens antagonism at NMDA receptors, surpassing the activity of KYNA [245]. This substitution not only stabilizes the molecule's conformation at the binding site but also alters its metabolic profile, with potential implications for clearance and half-life [286]. Gavestinel presents a related example, where the incorporation of sulfonamide groups enhances solubility and may support passage across the BBB, features that are critical for central nervous system activity [287]. While such modifications can improve receptor engagement and bioavailability, they also introduce challenges [288]. Altering chemical structures to enhance efficacy may inadvertently affect safety, particularly as compounds advance toward clinical evaluation [289]. Balancing these factors requires careful attention to the relationship between functional groups and biological outcomes [290]. Through studies of compounds like 7-CKA and Gavestinel, medicinal chemistry continues to identify structural features that support NMDA receptor modulation, offering a foundation for the development of new treatments targeting neurological disorders.

The challenges of translating quinoline-derived compounds into clinical success are illustrated by the case of Gavestinel. Developed to limit excitotoxic injury following stroke through NMDA receptor antagonism, Gavestinel advanced from preclinical studies with strong supporting data [291]. Yet, in clinical trials, it failed to produce meaningful improvements in patient outcomes, raising questions about the limitations of commonly used experimental models [292]. Stroke in humans presents variability in onset, severity, and timing that is difficult to replicate in animal studies [293]. Many preclinical trials rely on designs lacking adequate randomization, blinding, or statistical power, factors known to overestimate efficacy in stroke research [294]. Differences in treatment windows also complicate translation [295]. While preclinical models often apply interventions early, real-world scenarios involve delays, with irreversible damage frequently present before therapy begins [295]. Addressing these discrepancies requires trial designs that account for the complexity of human stroke and consider combining neuroprotective strategies with reperfusion approaches [296]. Without such adjustments, promising compounds remain at risk of falling short in clinical settings, regardless of structural refinement or pharmacological rationale.

The failure of IDO inhibitors in oncology trials has raised important considerations for the development of quinoline-based therapies [297]. Epacadostat, an IDO inhibitor evaluated for melanoma, did not meet its clinical endpoints, partly due to limited patient stratification and the absence of reliable biomarkers to predict treatment response [298]. Similar issues have been observed with Gavestinel in stroke studies, where variability in disease onset and delayed intervention may have obscured potential benefits [299]. These examples point to the value of using biomarkers—such as measures of KYN pathway activity or inflammatory cytokines—to guide patient selection and improve trial outcomes [300]. Combining KYNA analogs with immune checkpoint inhibitors or metabolic regulators may also help counteract compensatory mechanisms that reduce therapeutic effectiveness [301]. Trial designs that include real-time pharmacokinetic assessments, like cerebrospinal fluid analysis to verify central nervous system exposure, could support better decision-making during clinical evaluation [302]. Failures such as epacadostat’s also reflect the limitations of animal models, which often fall short of replicating the complexity of human pathophysiology [303,304]. Integrating techniques like metabolomics and single-cell RNA sequencing into preclinical research may help identify specific patient subgroups who are more likely to benefit from targeted quinoline derivatives.

Laquinimod, a quinoline-3-carboxamide derivative, offers a contrasting example of how molecular design can align with disease context to support therapeutic development [305]. In multiple sclerosis, where treatment focuses on managing chronic inflammation leading to neurodegeneration rather than responding to acute injury, laquinimod’s ability to reduce pro-inflammatory cytokines and support neuronal preservation has led to more favorable outcomes compared to agents like Gavestinel [306]. Unlike stroke, where delays in intervention often limit the impact of neuroprotective strategies, the progressive nature of multiple sclerosis provides a broader window in which immunomodulation may alter disease progression [307]. These differences raise an important question: how can molecular targets be matched more effectively to the underlying biology of a condition? Laquinimod’s selective focus on immune pathways contrasts sharply with the NMDA receptor antagonism of Gavestinel, highlighting the value of mechanisms that reflect the complexity of the disease environment. While setbacks in clinical translation are common, cases like laquinimod suggest that carefully tailored approaches, applied to appropriate patient groups, may improve the likelihood of success and offer meaningful advances in treating neurodegenerative disorders [308,309].

4.2. Mechanistic Trade-Offs

L-701,324 has drawn attention for its strong ability to block NMDA receptors and suppress excitatory neurotransmission [310]. In conditions such as epilepsy and neuropathic pain, this level of inhibition may offer therapeutic benefits [311]. Yet, the same mechanism that provides relief can also carry significant risks [312]. Cognitive disturbances, sedation, and symptoms resembling psychosis have been linked to excessive glutamatergic suppression, raising difficult questions about how far receptor blockade should go [313]. Should drug development focus on narrowing selectivity to avoid unintended effects, or might a broader range of activity offer advantages in disorders shaped by multiple interacting pathways? While some support the latter, NMDA receptor antagonists present clear limitations [314]. Even small deviations in targeting can disrupt neural function, underscoring the importance of precise molecular engagement [315]. The case of L-701,324 highlights this tension between therapeutic potential and safety [316]. Adjusting receptor affinity without tipping the balance too far remains a central challenge [314]. As research moves forward, designing compounds that maintain effective modulation while minimizing disruption will be key to expanding the use of NMDA antagonists in clinical settings.

A growing strategy involves developing BBB-penetrant derivatives that build on the neuroprotective potential of KYNA while addressing its limited access to the central nervous system [49]. One example includes modifying KYNA with tert-butyl ester groups, which may improve its transport across the BBB before enzymatic processes release active KYNA within neural tissue [317]. Alongside these efforts, multi-target approaches are attracting interest, particularly for conditions shaped by overlapping biological pathways [318]. Tasquinimod offers a case in point, combining HDAC4 inhibition with aryl hydrocarbon receptor modulation to influence both immune responses and cellular growth [319]. Such dual-action strategies aim to address the complexity of disorders like cancer and autoimmune diseases, where inflammation, proliferation, and tissue damage converge [320]. Whether the goal is to strengthen the delivery of KYNA analogs or to design compounds that coordinate multiple mechanisms, the challenge lies in maintaining therapeutic benefits while controlling off-target effects [321]. Progress will depend on refining these scaffolds through systematic screening, predictive modeling, and careful pharmacokinetic evaluation [322]. Together with biomarker-informed clinical studies, these efforts may guide the development of quinoline-based therapies for neurological, oncological, and inflammatory conditions.

Quinoline derivatives are gaining attention for their ability to influence epigenetic mechanisms, particularly through the modulation of histone deacetylation and DNA methylation [323]. Tasquinimod, targeting HDAC4, has demonstrated potential in addressing both neurodegenerative conditions and cancer, while newer compounds are being designed to expand activity across additional HDAC and DNMT targets [324]. These effects may help restore tumor suppressor functions or regulate inflammatory pathways [325]. Genetic variation within the KYN pathway, including polymorphisms in IDOs and KMO, adds another layer of complexity by shifting the balance between protective and harmful metabolites [326]. Combining genotyping with metabolic profiling may guide treatment strategies [327]. Moving forward, refining these molecules will require careful structure-activity studies and genotype-based clinical trials.

Recent findings also underscore the potential of lipid-based nanoparticle systems to improve the delivery of quinoline derivatives across the BBB [328]. For instance, encapsulating these molecules in lipid vesicles can mitigate their rapid clearance, thereby increasing CNS bioavailability [329]. This strategy not only allows for sustained drug release but also reduces off-target toxicity—advances that could reinvigorate clinical interest in repurposing or refining existing quinoline scaffolds [330]. In parallel, polymeric nanoparticles and biomimetic vesicles such as exosome-based carriers are emerging as next-generation vehicles for transporting hydrophilic or ionizable quinoline species [331]. By tailoring particle size, surface charge, and release kinetics, researchers can customize how these agents distribute and act in vulnerable CNS regions. Nanotechnology offers promising avenues to overcome the delivery challenges of polar quinoline derivatives like KYNA. By encapsulating these molecules in exosomes or polymeric nanoparticles, it is possible to enhance their stability, improve BBB penetration, and achieve targeted release at the site of action. This advanced delivery strategy not only increases local drug concentration but also minimizes systemic exposure, paving the way for more effective neuroprotective therapies. Incorporating such advanced delivery mechanisms will be crucial for translating preclinical ‘hits’ into viable, patient-friendly therapeutics.

5. Next-Generation Kynurenic Acid (KYNA) Analogues: The SZR Series

Structure–activity relationship (SAR) studies yield SZR derivatives with improved pharmacological profiles [332]. SZR-72 shows enhanced neuroprotection, effective blood–brain barrier (BBB) penetration, and behavioral modulation [333,334,335]. SZR-104 displays high BBB permeability and neuroprotective effects in sepsis models [47,336]. SZRG-21 demonstrates the effect on motor activity and emotional behavior [335]. SZR-109 stands out for its strong BBB penetration, suppression of TNF-α, upregulation of TSG-6, and anti-convulsant activity [49,337,338]. However, SZR-73, despite improving mitochondrial function and reducing systemic inflammation in sepsis, does not restore microcirculation, limiting its utility [221]. SZR-105, while highly BBB-permeable and anti-inflammatory, requires further validation for long-term safety [49,337]. Prioritizing SZR-81 may be premature due to poor BBB penetration, although its antidepressant-like effects and neuroprotective potential are promising [339]. Advancing lead optimization may benefit from synergistic strategies, such as combining these analogs with IDO inhibitors to better modulate the KYN pathway and enhance therapeutic efficacy.

Table 4. Kynurenic acid (KYNA) analogues from the SZR Series: atructural variations and pharmacological insights. The primary SZR-series analogues derived from KYNA are summarized here, highlighting their structural modifications and core pharmacological properties. The data emphasize their therapeutic relevance in excitotoxicity, neurodegenerative diseases, and related conditions, with references provided for deeper investigation.

	Compounds	Main characteristics	Ref.
	SZR-72	BBB penetration – effectively crosses the blood–brain barrier, enhancing its therapeutic potential in the CNS Neuroprotective effect – Offers enhanced neuroprotection, reduces brainstem c-fos, and induces therapeutic hypothermia Behavioral effects – Alters motor and exploratory behaviors, reducing vertical activity and affecting curiosity-linked emotional and motor responses	[334,335] [333,334] [335]
	SZR-73	Mitochondrial function enhancement – Enhances mitochondrial respiration and ATP production, improving complex I- and II-linked OXPHOS in a rodent sepsis model Systemic inflammatory activation reduction – Reduces systemic inflammation in sepsis, lowering ET-1, IL-6, NT levels, and XOR activity Microcirculatory Effects – Improves mitochondrial function but does not restore microcirculation, unlike KYNA, which improves microvascular perfusion in sepsis	[221] [221] [221]
	SZR-81	Antidepressant-like effects – Reduces immobility and increasing swimming in FST via serotonin 5-HT system involvement BBB permeability – Poor BBB penetration or metabolic alteration before reaching the CNS Neuroprotective potential– To be explored for use in stroke, neurodegenerative diseases, and inflammatory conditions	[339] [339] [340]
	SZR-104	High permeability through the blood – Shows high BBB permeability, surpassing KYNA and analogues Neuroprotective effects in sepsis – Demonstrates neuroprotection in septic rodents, reducing BBB disruption and CNS mitochondrial dysfunction Influence on motor behavior – Increases horizontal exploration, indicating BBB penetration and retention of KYNA-like effects on motor-related curiosity and emotional behavior	[49] [336] [335]
	SZR-105	High BBB penetrability – Significantly better BBB permeability than KYNA and earlier analogues due to its dual cationic side chains Potent anti-inflammatory effects – Suppresses TNF-α production and strongly induces TSG-6 Neuroprotective activity in CNS models – Reduces cortical spreading depression propagation in migraine models	[49] [337] [338]
	SZR-109	Enhanced BBB penetration – penetrate the BBB more effectively than KYNA Neuroprotective effects –Suppresses pro-inflammatory TNF-α production and upregulates TSG-6 Anti-convulsant activity – prevents or diminishes seizure-like activity in the brain	[49] [337] [338]
	SZRG-21	BBB penetration – Demonstrated efficacy in reducing cytokine levels in colitis models Impact on motor activity – Alter motor activity and exploratory behavior Emotional and behavioral modulation – Affect emotional functions such as motor-associated curiosity and emotions	[335] [335] [335]

ATP, adenosine triphosphate; BBB, blood-brain barrier; CNS, central nervous system; ET-1; endothelin-1; FST, forced swim test; 5-HT, 5-hydroxytryptamine; IL-6, interleukin 6; KYNA, kynurenic acid; NT, N-terminal peptide; OXPHOS, oxidative phosphorylation; TNF-α, tumor necrosis factor-alpha; TSG-6, tumor necrosis factor-stimulated gene-6; XOR, xanthine oxidoreductase.

Table 4. Kynurenic acid (KYNA) analogues from the SZR Series: atructural variations and pharmacological insights. The primary SZR-series analogues derived from KYNA are summarized here, highlighting their structural modifications and core pharmacological properties. The data emphasize their therapeutic relevance in excitotoxicity, neurodegenerative diseases, and related conditions, with references provided for deeper investigation.

	Compounds	Main characteristics	Ref.
	SZR-72	BBB penetration – effectively crosses the blood–brain barrier, enhancing its therapeutic potential in the CNS Neuroprotective effect – Offers enhanced neuroprotection, reduces brainstem c-fos, and induces therapeutic hypothermia Behavioral effects – Alters motor and exploratory behaviors, reducing vertical activity and affecting curiosity-linked emotional and motor responses	[334,335] [333,334] [335]
	SZR-73	Mitochondrial function enhancement – Enhances mitochondrial respiration and ATP production, improving complex I- and II-linked OXPHOS in a rodent sepsis model Systemic inflammatory activation reduction – Reduces systemic inflammation in sepsis, lowering ET-1, IL-6, NT levels, and XOR activity Microcirculatory Effects – Improves mitochondrial function but does not restore microcirculation, unlike KYNA, which improves microvascular perfusion in sepsis	[221] [221] [221]
	SZR-81	Antidepressant-like effects – Reduces immobility and increasing swimming in FST via serotonin 5-HT system involvement BBB permeability – Poor BBB penetration or metabolic alteration before reaching the CNS Neuroprotective potential– To be explored for use in stroke, neurodegenerative diseases, and inflammatory conditions	[339] [339] [340]
	SZR-104	High permeability through the blood – Shows high BBB permeability, surpassing KYNA and analogues Neuroprotective effects in sepsis – Demonstrates neuroprotection in septic rodents, reducing BBB disruption and CNS mitochondrial dysfunction Influence on motor behavior – Increases horizontal exploration, indicating BBB penetration and retention of KYNA-like effects on motor-related curiosity and emotional behavior	[49] [336] [335]
	SZR-105	High BBB penetrability – Significantly better BBB permeability than KYNA and earlier analogues due to its dual cationic side chains Potent anti-inflammatory effects – Suppresses TNF-α production and strongly induces TSG-6 Neuroprotective activity in CNS models – Reduces cortical spreading depression propagation in migraine models	[49] [337] [338]
	SZR-109	Enhanced BBB penetration – penetrate the BBB more effectively than KYNA Neuroprotective effects –Suppresses pro-inflammatory TNF-α production and upregulates TSG-6 Anti-convulsant activity – prevents or diminishes seizure-like activity in the brain	[49] [337] [338]
	SZRG-21	BBB penetration – Demonstrated efficacy in reducing cytokine levels in colitis models Impact on motor activity – Alter motor activity and exploratory behavior Emotional and behavioral modulation – Affect emotional functions such as motor-associated curiosity and emotions	[335] [335] [335]

ATP, adenosine triphosphate; BBB, blood-brain barrier; CNS, central nervous system; ET-1; endothelin-1; FST, forced swim test; 5-HT, 5-hydroxytryptamine; IL-6, interleukin 6; KYNA, kynurenic acid; NT, N-terminal peptide; OXPHOS, oxidative phosphorylation; TNF-α, tumor necrosis factor-alpha; TSG-6, tumor necrosis factor-stimulated gene-6; XOR, xanthine oxidoreductase.

5.1. SAR-Driven Innovations

In-depth SAR investigations reveal how subtle modifications to the KYNA core can profoundly affect receptor affinity and metabolic traits [341]. SZR-72, for instance, features a small methyl group that contributes to its enhanced neuroprotective effects, blood–brain barrier penetration, and behavioral modulation—suggesting that subtle steric modifications may play a significant role in optimizing CNS-targeted activity [335]. Meanwhile, SZR-104's C3 addition of the polar ring system demonstrates how introducing electronegative groups can enhance BBB permeability and support neuroprotection, especially in systemic inflammatory conditions [335]. By tweaking these chemical features—adding a methyl here, attaching a ring system there—researchers can systematically fine-tune key pharmacological properties like potency and half-life [342]. Such directed alterations reflect a deeper understanding of how receptor-ligand interactions depend on precise spatial and electronic configurations . In some cases, these modifications not only boost the BBB permeability but also reduce off-target binding, mitigating potential side effects [39]. Additionally, selecting the right functional group can influence polarity and solubility, traits that shape oral bioavailability [343]. Together, these iterative design strategies exemplify the power of SAR-driven innovations to optimize molecules for both efficacy and safety [344]. Beyond SZR-72 and SZR-104, further explorations could unleash even more advanced analogues that are fine-tuned to specific therapeutic goals. As we learn more, SAR mapping remains a cornerstone of rational drug discovery for KYNA derivatives.

Among the ever-growing list of KYNA analogues, SZRG-21 and SZR-109 stand out for their distinct therapeutic profiles in vivo [335,338]. Meanwhile, SZR-72, SZR-104, and SZRG-21 influence motor-associated curiosity and emotional behavior, implying broader neuromodulatory effects [335]. On the other hand, SZR-109 exhibits potent neuroprotective properties, notably suppressing TNF-α production and upregulating TSG-6 [337]. Its ability to effectively penetrate the blood–brain barrier and its anti-convulsant effects—preventing seizure-like activity—further highlight its therapeutic potential in central nervous system disorders [49,338]. The contrasting profiles of these analogues underscore how strategic SAR modifications can yield compounds tailored to specific pathophysiologies. While SZRG-21 appears suited to modulate behavioral aspects, SZR-109 is structurally optimized for neuroprotection [335,338]. These findings emphasize the flexibility of the KYNA scaffold, which allows for fine-tuned substituents to address diverse pathological targets. Further studies on their binding affinities and pharmacokinetics may unlock new therapeutic applications and refine their clinical relevance. Ultimately, SZRG-21 and SZR-109 exemplify how SAR-guided innovation can push the boundaries of KYNA-based therapeutics.

5.2. Translational Barriers

Despite ongoing refinements to KYNA analogues, multiple translational barriers must be addressed before these compounds can achieve widespread clinical utility. Prodrug strategies or nanoparticle delivery systems could potentially mitigate such clearance problems, yet these approaches introduce their own complexities in formulation and manufacturing [345,346]. On another front, SZR-105 demonstrates considerable promise but poses its own safety concern: off-target kinase inhibition [49,347]. Even minor structural tweaks can inadvertently shift binding toward other enzymes or receptors, jeopardizing patient safety [335]. Balancing pharmacological potency with a clean off-target profile is therefore a central challenge in modern drug development [348,349]. Medicinal chemists must undertake detailed SAR investigations, systematically exploring substituents and functional groups to minimize toxicity while preserving therapeutic efficacy [350]. Such iterative optimization demands close collaboration among chemists, pharmacologists, and toxicologists, each focusing on a different aspect of a molecule’s life cycle [351]. By carefully addressing problems like rapid clearance and unintended kinase inhibition, researchers can pave the way for safer, longer-lasting KYNA-based treatments that ultimately improve patient outcomes. This section may be divided by subheadings. It should provide a concise and precise description of the experimental results, their interpretation, as well as the experimental conclusions that can be drawn.

5.3. Path to Lead Optimization

Achieving an optimal lead among KYNA analogues calls for balancing efficacy, selectivity, and favorable pharmacokinetics [352]. Balanced profiles are critical in translational research, where the nuances of absorption, distribution, metabolism, and excretion (ADME) intersect with complex biological pathways [353]. High bioavailability ensures that the compound can be administered conveniently, improving patient compliance and potentially reducing dosing frequency [354]. Meanwhile, precise receptor selectivity helps mitigate adverse effects by limiting unwanted off-target binding [355]. These attributes underscore the importance of methodical SAR evaluations, wherein subtle modifications to the parent scaffold can bolster both pharmacodynamics and pharmacokinetics [356]. Complementary techniques like computational modeling and in vitro assays further expedite the refinement process, shedding light on metabolic pathways and guiding structural tweaks [357]. By identifying leads in the SZR series, researchers can streamline development cycles and reduce the risk of late-stage failures in clinical trials [358]. Ultimately, focusing on candidates that marry oral bioavailability with selective receptor engagement represents a viable strategy to usher KYNA-based therapies toward their full therapeutic potential.

Adopting combinatorial approaches that integrate multiple therapeutic strategies can heighten the efficacy of KYNA-based treatments [359]. One promising avenue involves combining SZR analogs, designed to selectively modulate GPR35 or NMDA receptors, with established IDO inhibitors that curtail the overall flux through the KYN pathway [360]. By partially blocking the production of downstream metabolites, IDO inhibitors reduce the burden of neurotoxic or immunomodulatory intermediates, thus creating a biochemical context where KYNA analogs may exert stronger protective or immunoregulatory effects [361]. This two-pronged tactic could help maintain stable levels of beneficial metabolites like KYNA, while simultaneously minimizing harmful byproducts, leading to more robust interventions in neurodegenerative or inflammatory conditions [362]. Preclinical data suggests that synergy may stem from the interplay between decreased KYN production and amplified receptor engagement by the analogs [363]. However, identifying optimal drug combinations will require meticulous dose-response studies and toxicological evaluations [364]. In particular, attention to pharmacokinetic profiles, such as how these agents interact or compete for metabolic pathways, is essential to avoid unintended consequences [365]. Ultimately, harnessing a combinatorial approach like SZR analogs plus IDO inhibitors illustrates the potential of integrated interventions targeting multiple points along the KYN pathway [366]. Such strategies may yield tangible clinical outcomes that surpass those achievable by single-agent therapies alone.

6. Patents

P1500356; PCT/HU2017?000014; EP17759330.8A; US15/082,099: WO 2017149333; A1 2017090. P1500356; PCT/HU2016/050034; US 10,857,236B2 (2020); WO2017021748 (EU).