Antitubercular activity of 2-mercaptobenzothiazole derivatives targeting Mycobacterium tuberculosis type II NADH dehydrogenase.

Mycobacterium tuberculosis (Mtb) type II NADH dehydrogenase (NDH-2) transports electrons into the mycobacterial respiratory pathway at the cost of reduction of NADH to NAD+ and is an attractive drug target. Herein, we have synthesised a series of 2-mercaptobenzothiazoles (C1-C14) and evaluated their anti-tubercular potential as Mtb NDH-2 inhibitors. The synthesised compounds C1-C14 were evaluated for MIC90 and ATP depletion against Mtb H37Ra, M. bovis, and Mtb H37Rv mc2 6230. Compounds C3, C4, and C11 were found to be the active molecules in the series and were further evaluated for their MIC90 against Mtb-resistant strains and for their bactericidal potential against Mtb H37Rv mc26230. The Peredox-mCherry-expressing Mtb strain was used to examine whether C3, C4, and C11 possess NDH-2 inhibitory potential. Furthermore, cytotoxicity analysis against HepG2 displayed a safety index (SI) of >10 for C3 and C4. To get an insight into the mode of interaction at NDH-2, we have performed computational analysis of our active compounds.

Cytochrome bd oxidase: an emerging anti-tubercular drug target.

Cytochrome bd (cyt-bd) oxidase, one of the two terminal oxidases in the Mycobacterium tuberculosis (Mtb) oxidative phosphorylation pathway, plays an indispensable role in maintaining the functionality of the metabolic pathway under stressful conditions. However, the absence of this oxidase in eukaryotic cells allows researchers to select it as a potential drug target for the synthesis of anti-tubercular (anti-TB) molecules. Cyt-bd inhibitors have often been combined with cytochrome bcc/aa3 super-complex inhibitors in anti-TB drug regimens to achieve a desired bactericidal response. The functional redundancy between both the terminal oxidases is responsible for this. The cryo-EM structure of cyt-bd oxidase from Mtb (PDB ID: 7NKZ) further accelerated the research to identify its inhibitor. Herein, we have summarized the reported anti-TB cyt-bd inhibitors, insight into the rationale behind targeting cyt-bd oxidase, and an outline of the architecture of Mtb cyt-bd oxidase.

DNA topoisomerases as a drug target in Leishmaniasis: Structural and mechanistic insights.

Leishmaniasis, caused by a protozoan parasite, is among humanity's costliest banes, owing to the high mortality and morbidity ratio in poverty-stricken areas. To date, no vaccine is available for the complete cure of the disease. Current chemotherapy is expensive, has undesirable side effects, and faces drug resistance limitations and toxicity concerns. The substantial differences in homology between leishmanial DNA topoisomerase IB compared with the human counterparts provided a new lead in the study of the structural determinants that can be targeted. Several research groups explored this molecular target, trying to fill the therapeutic gap, and came forward with various anti-leishmanial scaffolds. This article is a comprehensive review of knowledge about topoisomerases as an anti-leishmanial drug target and their inhibitors collected over the years. In addition to information on molecular targets and reported scaffolds, the review details the structure-activity relationship of described compounds with leishmanial Topoisomerase IB. Moreover, the work also includes information about the structure of the inhibitors, showing common interacting residues with leishmanial topoisomerases that drive their mode of action towards them. Finally, in search of topoisomerase inhibitors at the stage of clinical trials, we have listed all the drugs that have been in clinical trials against leishmaniasis.

Design, synthesis, and biological evaluation of 3,3'-diindolylmethane N-linked glycoconjugate as a leishmanial topoisomerase IB inhibitor with reduced cytotoxicity.

Leishmaniasis, one of the neglected diseases, ranks second to malaria in the cause of parasitic mortality and morbidity. The present chemotherapeutic regimen faces the limitations of drug resistance and toxicity concerns, raising a great need to develop new chemotherapeutic leads that are orally administrable, potent, non-toxic, and cost-effective. Several research groups came forward to fill this therapeutic gap with new classes of active compounds against leishmaniasis, one such being 3,3'-diindolylmethane (DIM) derivatives. We tried to link this concept with another promising approach of glycoconjugation to study how glycosylated groups work differently from non-glycosylated ones. In the present study, a series of 3,3'-DIM derivatives have been synthesized and screened for their anti-leishmanial potency on Leishmania donovani promastigotes. Next, we synthesized the ß-N,N' glycoside of potent compound 3d using indole-indoline conversion, Fischer-type glycosylation, 2,3-dichloro-5,6-dicyano-1,4-benzoquionone (DDQ) oxidation, and molecular iodine catalyzed coupling with a suitable aldehyde in reasonable overall yield. The biological evaluation revealed that glycosides had reduced cytotoxic effects on the J774A.1 macrophage cell line. The enzyme inhibition study confirms that the glycoside derivatives have significant inhibitory activity against the leishmanial topoisomerase IB enzyme. Molecular docking further displayed the better binding efficiency of glycoside 13 with the target enzyme, suggesting the involvement of more H-bond interactions in the case of glycosides as compared to free drugs. Therefore, this work helps in proposing the fact that the addition of sugar moieties adds some favorable characteristics to free inhibitors, making it a promising approach for future clinical diagnostic and therapeutic applications, which can prove to be a valuable arsenal in combating such neglected diseases.

Visible light induced regioselective C-3 thiocyanation of imidazoheterocycles through naphthalimide dye based photoredox catalysis.

A visible light induced C-3 thiocyanation of imidazo[1,2-a]pyridines by using a naphthalimide based photoredox catalyst has been reported. Tolerance of electron withdrawing and donating groups at different positions of the imidazo[1,2-a]pyridine ring led to a wide substrate accessibility of this method. This methodology is further reproducible with other heterocycles like benzo[d]imidazo[2,1-b]thiazoles, indoles, azaindoles, and anilines.