Current Topics in Medicinal Chemistry - Volume 21, Issue 18, 2021

Introduction: Tuberculosis is a life-threatening disease, and the drugs discovered during the era of 1950 and 1970 are found to be inefficient due to emergent MDR and XDR-TB. Tuberculosis is difficult to treat due to the development of antibiotic resistance. ATP synthase consists of two units, F1 and F0 units. These are present in the cytoplasm and membrane of mitochondria, respectively. F1 unit comprises of a, b, and c subunit while F0 subunit has α, β, γ, δ, ε subunits. Bedaquiline was the first approved ATP synthase inhibitor in 2012 by USFDA. Methods: Recent literature from 2005-2020 were collected using Pubmed with the keywords ATP synthase inhibitor, bedaquiline derivatives, tuberculosis. The work describing detailed analyses of bedaquiline (BDQ) was included in the current work, and others were excluded. Results: ATP production occurs via the ATP synthase enzyme, leading to the growth and multiplication of mycobacteria. BDQ inhibits the mycobacterium ATP synthase enzyme, a heteropolymeric complex consisting of two subunits, but it does not interfere with mammalian ATP synthase. Bedaquiline (BDQ) has become a drug of choice in treating MDR-TB and helps in reducing the treatment span. Recently observed triple mutation as wtLeu59A→mtVal59A; wtIle66A→mtMet66A and wtGlu61B→mtAsp61B of ATP synthase led to decrease BDQ binding affinity; thus, researchers are putting efforts for its newer derivative discovery. Conclusion: ATP synthase inhibitor could be an alternative approach for better treatment of tuberculosis. Herein we discussed the recent advancements in the development of newer analogues of BDQ with its future perspectives.

Cancers, a set of genetic diseases that can change the behavior and cell growth in body tissues, are the second leading cause of death across the world. Several treatment approaches, such as radiation, immunotherapy, and chemotherapy, can be applied to cure cancer, and among them, chemotherapy is one of the primary treatments for cancer, in which chemotherapeutic drugs are used. Great achievements have been made in the development of novel anticancer agents, but drug resistance is usually generated quickly, making overcoming drug resistance or developing more effective anticancer agents an imperative challenge. β-Lactones (2-oxetanones) are chemically diverse and often referred to as privileged structures for the discovery of new drugs, including anticancer agents. Marizomib (Salinosporamide A), a naturally occurring β-lactone proteasome inhibitor derived from the marine actinobacterium Salinispora tropica, has been termed as an orphan drug against multiple myeloma. Therefore, β-lactones are useful scaffolds for the discovery of novel anticancer agents. This review is an endeavour to highlight the advances in β-lactone derivatives with anticancer potential. The synthetic strategies, structure-activity relationships, as well as modes of action, are also discussed to pave the way for further rational design.

Cancer is a life-threatening destructive disease. In the past several decades, the incidence of cancer has been dramatically increased mostly due to lifestyle changes. Chemotherapy plays an important role in the treatment of cancer, but the development of resistance against chemotherapeutic agents, the side effects, and non-specific toxicity threatens the efficiency of anticancer agents. Accordingly, it is important to develop novel anticancer drugs. Beyond the classical antibacterial activity, macrolides also demonstrated potential effects against both drug-sensitive and drug-resistant cancers through modulating diverse targets and signaling pathways, so rational design of macrolides may generate valuable therapeutic interventions for the treatment of cancers. The purpose of the present review article is to outline the current developments in macrolides with an emphasis on anticancer activity, structure-activity relationships, and mechanisms of action to lay the path for the development of novel macrolide anticancer candidates.

The development of novel anticancer agents with high efficiency is of great importance due to the severe anticancer scenario of the currently used drugs. Dimerization is a useful method to develop new drug candidates with a broad biological spectrum, enhanced activity and potency to overcome drug resistance. A wide variety of bis-triazole-containing compounds have been developed with improved properties compared with their parent compounds. These derivatives could inhibit tumor proliferation, invasion and metastasis, revealing their potential as putative anticancer candidates. This review covers the recent advances of bis-triazole-containing compounds as anticancer candidates, and the structure-activity relationship are also discussed to set up the direction for the design and development of bis-triazole-containing compounds with higher efficiency.

Breast cancer is the most frequent female cancer and one of the leading causes of cancer death in women. There are many chemotherapy agents available for the treatment of breast cancer. Still, the current therapeutic options have not fulfilled the desired outcomes, especially for drug-resistant breast cancer therapy. Thus, there is an urgent need to develop novel anti-breast cancer agents. Coumarin is ubiquitous in natural and synthetic bioactive compounds, and coumarin derivatives readily interact with a variety of enzymes and receptors in breast cancer cells. Moreover, the coumarin-based irosustat as the first-generation steroid sulfatase inhibitor in breast cancer is under clinical evaluation, revealing the potential of coumarin derivatives as novel anti-breast cancer agents. This review aims to describe the recent development of natural and synthetic coumarin derivatives with anti-breast cancer potential, covering the articles published from 2015 to 2020.