SAR based Review on Diverse Heterocyclic Compounds with Various Potential Molecular Targets in the Fight against COVID-19: A Medicinal Chemist Perspective.

Coronavirus disease (COVID-19) was reported to be transmitted from bats to humans and, became a pandemic in 2020. COVID-19 is responsible for millions of deaths worldwide and still, the numbers are increasing. Further, despite the availability of vaccines, mutation in the virus continuously poses a threat of re-emergence of the more lethal form of the virus. So far, the repurposing of drugs has been exercised heavily for the identification of therapeutic agents against COVID-19, which led FDA to approve many drugs for the same e.g., remdesivir, favipiravir, ribavirin, etc. The anti-COVID drugs explored via other approaches include nirmatrelvir (used in combination with ritonavir as Paxlovid), tixagevimab and cilgavimab (both used in combination with each other) and others. However, these approved drugs failed to achieve a significant clinical outcome. Globally, natural bioactive have also been explored for anti-COVID-19 effects, based on their traditional medicinal values. Although the clinical findings suggest that FDA-approved drugs and natural bioactives can help reducing the overall mortality rate but the significant clinical outcome was not achieved. Therefore, the focus has been shifted towards new drug development. In line with that, a lot of work has been done and still going on to explore heterocyclic compounds as potent anti- COVID-19 drugs. Several heterocyclic scaffolds have been previously reported with potent antiinflammatory, anticancer, anti-viral, antimicrobial and anti-tubercular effects. Few of them are under consideration for clinical trials whereas others are under preclinical investigation. Hence, this review discusses the evidence of rationally designed and tested heterocyclic compounds acting on different targets against COVID-19. The present article will help the researches and will serve as a pivotal resource in the design and development of novel anti-COVID-19 drugs.

Role of NLRP3 Inflammasome and Its Inhibitors as Emerging Therapeutic Drug Candidate for Alzheimer's Disease: a Review of Mechanism of Activation, Regulation, and Inhibition.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. The etiology and pathology of AD are complicated, variable, and yet to be completely discovered. However, the involvement of inflammasomes, particularly the NLRP3 inflammasome, has been emphasized recently. NLRP3 is a critical pattern recognition receptor involved in the expression of immune responses and has been found to play a significant role in the development of various immunological and neurological disorders such as multiple sclerosis, ulcerative colitis, gout, diabetes, and AD. It is a multimeric protein which releases various cytokines and causes caspase-1 activation through the process known as pyroptosis. Increased levels of cytokines (IL-1ß and IL-18), caspase-1 activation, and neuropathogenic stimulus lead to the formation of proinflammatory microglial M1. Progressive researches have also shown that besides loss of neurons, the pathophysiology of AD primarily includes amyloid beta (Aß) accumulation, generation of oxidative stress, and microglial damage leading to activation of NLRP3 inflammasome that eventually leads to neuroinflammation and dementia. It has been suggested in the literature that suppressing the activity of the NLRP3 inflammasome has substantial potential to prevent, manage, and treat Alzheimer's disease. The present review discusses the functional composition, various models, signaling molecules, pathways, and evidence of NLRP3 activation in AD. The manuscript also discusses the synthetic drugs, their clinical status, and projected natural products as a potential therapeutic approach to manage and treat NLRP3 mediated AD.