Current Topics in Medicinal Chemistry - Volume 21, Issue 6, 2021

Coronaviruses (CoVs) are enveloped positive-stranded RNA viruses with spike (S) protein projections that allow the virus to enter and infect host cells. The S protein is a key virulence factor determining viral pathogenesis, host tropism, and disease pathogenesis. There are currently diverse corona viruses that are known to cause disease in humans. The occurrence of Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), as fatal human CoV diseases, has induced significant interest in the medical field. The novel coronavirus disease (COVID-19) is an infectious disease caused by a novel strain of coronavirus (SAR-CoV-2). The SARS-CoV2 outbreak has been evolved in Wuhan, China, in December 2019, and identified as a pandemic in March 2020, resulting in 53.24 M cases and 1.20M deaths worldwide. SARS-CoV-2 main proteinase (M^Pro), a key protease of CoV-2, mediates viral replication and transcription. SARS-CoV-2 M^Pro has been emerged as an attractive target for SARS-CoV-2 drug design and development. Diverse scaffolds have been released targeting SARS-CoV-2 M^Pro. In this review, we culminate the latest published information about SARS-CoV-2 main proteinase (M^Pro) and reported inhibitors.

1,2,3-Triazole, a five-membered heterocyclic nucleus, is widely recognized as a key chromophore of great value in medicinal chemistry for delivering compounds possessing innumerable biological activities, including antimicrobial, antitubercular, antidiabetic, antiviral, antitumor, antioxidants, and anti-inflammatory activities. Mainly, in the past years, diverse conjugates carrying this biologically valuable core have been reported due to their attractive fungicidal potential and potent effects on various infective targets. Hence, hybridization of 1,2,3-triazole with other antimicrobial pharmacophores appears to be a judicious strategy to develop new effective anti-fungal candidates to combat the emergence of drug-sensitive and drug-resistant infectious diseases. Thus, the current review highlights the recent advances of this promising category of 1,2,3-triazole-containing hybrids incorporating diverse varieties of bioactive heterocycles such as conozole, coumarin, imidazole, benzimidazole, pyrazole, indole, oxindole, chromene, pyrane, quinazoline, chalcone, isoflavone, carbohydrates, and amides. It underlies their inhibition behavior against a wide array of infectious fungal species during 2015-2020.

Docking is in demand for the rational computer aided structure based drug design. A review of docking methods and programs is presented. Different types of docking programs are described. They include docking of non-covalent small ligands, protein-protein docking, supercomputer docking, quantum docking, the new generation of docking programs and the application of docking for covalent inhibitors discovery. Taking into account the threat of COVID-19, we present here a short review of docking applications to the discovery of inhibitors of SARS-CoV and SARS-CoV-2 target proteins, including our own result of the search for inhibitors of SARS-CoV-2 main protease using docking and quantum chemical post-processing. The conclusion is made that docking is extremely important in the fight against COVID-19 during the process of development of antivirus drugs having a direct action on SARS-CoV-2 target proteins.

Human tuberculosis (TB) is primarily caused by Mycobacterium tuberculosis (Mtb) that inhabits inside and amidst immune cells of the host with adapted physiology to regulate interdependent cellular functions with intact pathogenic potential. The complexity of this disease is attributed to various factors such as the reactivation of latent TB form after prolonged persistence, disease progression specifically in immunocompromised patients, advent of multi- and extensivelydrug resistant (MDR and XDR) Mtb strains, adverse effects of tailor-made regimens, and drug-drug interactions among anti-TB drugs and anti-HIV therapies. Thus, there is a compelling demand for newer anti-TB drugs or regimens to overcome these obstacles. Considerable multifaceted transformations in the current TB methodologies and molecular interventions underpinning hostpathogen interactions and drug resistance mechanisms may assist to overcome the emerging drug resistance. Evidently, recent scientific and clinical advances have revolutionised the diagnosis, prevention, and treatment of all forms of the disease. This review sheds light on the current understanding of the pathogenesis of TB disease, molecular mechanisms of drug-resistance, progress on the development of novel or repurposed anti-TB drugs and regimens, host-directed therapies, with particular emphasis on underlying knowledge gaps and prospective for futuristic TB control programs.