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A series of 2,5-disubstituted benzimidazole derivatives was synthesized with the aim to identify compounds with potent anti-TB activity. All the compounds were screened in vitro against cultured Mycobacterium tuberculosis H 37 Rv strain and found to be exhibiting MIC 99 values in the range of 0.195-100 µM. Out of 43 synthesized compounds, two compounds 11h and 13e showed better anti-TB activity than the reference drug isoniazid., (© 2022 Wiley Periodicals LLC.)

Drug-resistance in mycobacterial infections is a major global health problem that leads to high mortality and socioeconomic pressure in developing countries around the world. From finding new targets to discovering novel chemical scaffolds, there is an urgent need for the development of better approaches for the cure of tuberculosis. Recently, energy metabolism in mycobacteria, particularly the oxidative phosphorylation pathway of cellular respiration, has emerged as a novel target pathway in drug discovery. New classes of antibacterials which target oxidative phosphorylation pathway either by interacting with a protein or any step in the pathway of oxidative phosphorylation can combat dormant mycobacterial infections leading to shortening of tuberculosis chemotherapy. Adenosine triphosphate synthase is one such recently discovered target of the newly approved antitubercular drug bedaquiline. Cytochrome bcc is another new target of the antitubercular drug candidate Q203, currently in phase II clinical trial. Research suggests that b subunit of cytochrome bcc, QcrB, is the target of Q203. The review article describes the structure, function, and importance of targeting QcrB throwing light on all chemical classes of QcrB inhibitors discovered to date. An understanding of the structure and function of validated targets and their inhibitors would enable the development of new chemical entities., (© 2021 Wiley Periodicals LLC.)

Tuberculosis, an airborne infectious disease, results in a high morbidity and mortality rate. The continuous emergence of TB resistance strains including MDR (multidrug-resistant tuberculosis), XDR (extensive drug-resistant tuberculosis), and especially TDR (totally drug-resistant tuberculosis) is a major public health threat and has intensified the need to develop new antitubercular agents. A natural product, curcumin, possesses diverse biological activities but suffers due to a lack of water solubility and bioavailability. To overcome these limitations, a series of 17 water-soluble monocarbonyl curcuminoids was synthesized and evaluated for antimycobacterial activity. All compounds exhibited good to moderate anti-TB activity with MIC 99 in the range of 3.12-25.0 µM, out of which 7c and 7p were found the most potent compounds with MIC 99 in the range of 3.12-6.25 µM. Furthermore, these compounds were observed to be nonhaemolytic, nontoxic, and stable under both physiological as well as reducing conditions. In-vitro metabolic stability data of the representative compound 7p with the human liver microsome revealed that these compounds possess a moderate metabolism with a half-life of 1.2 h and an intrinsic clearance of 1.12 ml/h/mg., (© 2021 Wiley Periodicals LLC.)

A persistent infection prolongs treatment duration and also enhances the chance of resistance development against antibiotics. Recently, a class of amphiphilic indole derivatives was discovered exhibiting bactericidal activity against both growing and nongrowing Mycobacterium bovis BCG (M. bovis BCG). These antibacterials are suggested to disturb the integrity and functioning of the cell membrane, a property that can help eradicate persistent organisms. This study article describes field-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of 79 amphiphilic indole derivatives. The aim of this QSAR study is to optimize this class of compounds for the development of more potent antimycobacterial agents. The results obtained indicate that steric interactions are crucial for antimycobacterial activity, while hydrogen bond donor groups participate negligibly in activity. The derived 3D-QSAR models showed acceptable r 2 (0.91) and q 2 (0.91) with a root mean squared error (RMSE) of 0.08. The models were cross-validated using the leave-one-out method. Applying the same QSAR model to another congeneric series of amphiphilic indoles externally validated the QSAR model. The model could appreciably predict the activity (pMIC 50 ) of this congeneric series of amphiphilic indoles, with an RMSE of 0.49, indicating the robustness of the model and its efficiency in predicting the potentially active compounds., (© 2020 Wiley Periodicals LLC.)

The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug-resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four-drug treatment regimen was introduced 40 years ago but the emergence of multidrug-resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti-TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug-target interactions, and their structure-activity relationship., (© 2019 Wiley Periodicals, Inc.)

The increasing drug resistance of Mycobacterium tuberculosis to the currently used drugs and HIV coinfection has caused alarm in the international scientific community. Subsequently, there is an urgent need for the development of new drug molecules with newer targets and with an alternative mechanism of action. Since the last 50 years, the same long-duration, multidrug treatment plan is being followed for the treatment of tuberculosis. The objective of this review article is to critically analyze the antitubercular potential of various classes of compounds (quinoline, diamine, quinolone, fluoroquinolone, quinone, nitroimidazole, terpenoid, isonicotinyl, oxazolidinone, pyrimidine, and purine), their possibility to be a future drug candidate, and latest information on the clinical status of some novel antitubercular compounds. Compounds such as moxifloxacin, PA824, and TMC207 are well tolerated and there is no adverse effect shown by them. Moxifloxacin and gatifloxacin shows cross-resistance to the currently used drugs while no cross-resistance observed in case of TMC207 and PA824. Some compounds like OPC67683 and PA824 are bactericidal in nature., (© 2012 Wiley Periodicals, Inc.)

The discovery of artemisinin from Chinese medicinal plant, Artemisia annua in 1971, opened a new era in the malarial chemotherapy. This discovery was the beginning of exploring peroxides as potential replacements for the traditional antimalarial drugs such as chloroquine and mefloquine. The structurally simple class of peroxides that emerged from these studies was the 1,2,4,5-tetraoxanes. This study describes the current status of tetraoxane-based antimalarials that show significant promises because of their artemisinin-like activity. Literature from 1999 has been critically reviewed and an attempt has been made to discuss various synthetic methods and structure–activity relationship study among the series of tetraoxane-based compounds., (© 2010 Wiley Periodicals, Inc.)

The discovery of artemisinin from Chinese medicinal plant, Artemisia annua in 1971, opened a new era in the malarial chemotherapy. This discovery was the beginning of exploring peroxides as potential replacements for the traditional antimalarial drugs such as chloroquine and mefloquine. The structurally simple class of peroxides that emerged from these studies was the 1,2,4,5-tetraoxanes. This study describes the current status of tetraoxane-based antimalarials that show significant promises because of their artemisinin-like activity. Literature from 1999 has been critically reviewed and an attempt has been made to discuss various synthetic methods and structure-activity relationship study among the series of tetraoxane-based compounds. © 2010 Wiley Periodicals, Inc. Med Res Rev.