Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Development of New Drugs to Treat Tuberculosis Based on the Dinitrobenzamide Scaffold

Tiago Delgado
ORCID logo ,
João Pais
ORCID logo ,
David Pires
,
Filipe Estrada
,
Rita Guedes
ORCID logo ,
Elsa Anes
ORCID logo ,
Luís Constantino
* ORCID logo
Version 1 : Received: 13 March 2024 / Approved: 14 March 2024 / Online: 14 March 2024 (11:12:33 CET)

A peer-reviewed article of this Preprint also exists.

Delgado, T.; Pais, J.P.; Pires, D.; Estrada, F.G.A.; Guedes, R.C.; Anes, E.; Constantino, L. Development of New Drugs to Treat Tuberculosis Based on the Dinitrobenzamide Scaffold. Pharmaceuticals 2024, 17, 559. Delgado, T.; Pais, J.P.; Pires, D.; Estrada, F.G.A.; Guedes, R.C.; Anes, E.; Constantino, L. Development of New Drugs to Treat Tuberculosis Based on the Dinitrobenzamide Scaffold. Pharmaceuticals 2024, 17, 559.

Abstract

Despite the efforts made to stop the tuberculosis (TB) epidemic, it still remains one of the leading causes of death from an infectious disease. Previous work in the group uncovered a new family of amides which showed promising activities against Mycobacterium tuberculosis. A closer look at the literature showed that these compounds are structurally related to the DNB family of DprE1 inhibitors, so, we decided to study a wide range of substituted amides and determine their activity, focusing on unexplored structures related to the dinitrobenzamides (DNB) found in the literature. To synthesize our library of compounds we started from 3,5-dinitrobenzoic acid to form the nitroaromatic core that is characteristic of the DNB’s, to which we then added linear or cyclic amine moieties. Additionally, the impact of terminal aromatic moieties was also assessed for some derivatives, via an ether, ester, or amide bond. In order to obtain the desired derivatives, multiple synthetic approaches were used, mainly focused on nucleophilic addition/elimination reactions, SN2 reactions and Mitsunobu reactions. The activity was impacted mainly by two structural features, the addition of an aromatic moiety as a terminal group and the type of the linker. The most interesting compounds exhibited activities comparable to isoniazid and DNB1. Computational studies were also performed aimed at understanding their possible interactions with DprE1. The most active compounds are a good starting point for further development, and we plan to study an extended family of compounds based in those structures.

Keywords

Tuberculosis; DprE1; DNB; TB; Nitrobenzamides

Subject

Medicine and Pharmacology, Pharmacy

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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