Menaquinone is one of the major lipoquinones involved in the respiratory chains of bacteria, which includes ubiquinone. Menaquinone is an essential component in the electron transfer process and ATP synthesis especially in some Gram-positive bacteria including Mycobacterium tuberculosis (M. Tb). However, mammals utilize ubiquinone in the analogous electron transfer processes, and do not synthesize menaquinone. In the biosynthesis of menaquinone, MenA is an important enzyme, which is involved in the conversion of 1,4-dihydroxy-2-napthoate to demethylmenaquinone via prenyl transferase activity. Therefore MenA is chosen as a drug target in determining the inhibitor. While designing and screening MenA inhibitors we observed that benzophenone derivatives showed high coordination with enzymes in transition state and interrupted the growth of M. Tb moderately. In addition, diphenyl ether derivatives also showed moderate MIC and IC50 results. Therefore, to improve the biological activity we synthesized a polymeric compound having both benzophenone and diphenyl ether groups. In addition, a hydrophilic functional group was introduced into the polymeric compound to enhance the biological activity. The synthesized polymeric inhibitor showed improved MIC and IC50 values to inhibit the M. tb infection.

Gap junctions (GJs) made of connexin-43 (Cx43) are important for the conduction of electrical impulses in the heart. Modulation of Cx43 activity may be useful in the treatment of cardiac arrhythmias and other dysfunctions. Search of novel GJ modulating agents using molecular docking approach allows to predict the binding affinities that often significantly differ from experimentally estimated their potencies. The objective of this study was to demonstrate that Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using the QSAR model and molecular docking, we evaluated the known Cx43 GJ inhibitors, suggested a new one, and tested it experimentally. Our QSAR model predicted the concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds and estimated the correlation between predicted and experimental IC50ies (pIC50 and eIC50). This led to suggestion of monocyclic monoterpene d-limonene as putative Cx43 inhibitor with pIC50 = 1.07. In turn, dual whole-cell patch-clamp measurements provided eIC50=1.41. The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR model well correlated with their eIC50ies (R = 0.88) in contrast to pIC50s obtained from molecular docking (R = 0.42). However, the molecular docking suggested that inhibitor potency may depend on their docking sites on Cx43.

Background: Reducing the impact of malaria is a key to achieving the sustainable development goals which are geared towards eradicating the disease. The main objective of this study was to synthesize, determine the efficacy and safety of antiplasmodial hybrid drug comprising of sarcosine and aniline derivative for management of plasmodial infections. Results: The hybrid drug was synthesized by adding thionyl chloride to sarcosine in order to form acyl chloride which was then added to aniline to form sarcosine-aniline hybrid molecule. The IC50 of sarcosine-aniline hybrid was 44.80 ± 4.70 ng/ml compared to that of aniline derivative which was 22.86 ± 1.26 ng/ml. The IC50 of control drugs were 2.63 ± 0.38 ng/ml, 5.69 ± 0.39 ng/ml for artesunate and chloroquine respectively. There was a significant difference between IC50 of sarcosine-aniline hybrid and aniline derivative (P<0.05). There was also a significant difference between sarcosine-aniline hybrid and standard drugs used to treat malaria including artesunate and chloroquine (P<0.05). The ED50 of sarcosine-aniline hybrid drug was 6.49mg/kg compared to that of aniline derivative which was 3.61mg/kg. The ED50 of control drugs were 3.56 mg/kg, 2.94mg/kg and 1.78 mg/kg for artesunate-aniline hybrid, artesunate and chloroquine respectively. There was a significant difference (P<0.05) between ED50 of sarcosine-aniline hybrid and both controls such as aniline derivative, artesunate, artesunate-aniline hybrid and chloroquine. Cytotoxicity results revealed that sarcosine-aniline hybrid was safe to vero cells with a CC50 of 50.18±3.53µg/ml. Sarcosine-aniline hybrid was significantly less toxic compared to artesunate, chloroquine and doxorubicin. Sarcosine-aniline hybrid was also safe to mice. Conclusion: Therefore, covalent bitherapy should be used in drug development for drug resistance mitigation.