Mustapha Suleiman

It has been more than four years since the first report of SARS-CoV-2, and humankind has experienced a pandemic with an unprecedented impact. Moreover, the new variants have made the situation even worse. Among viral enzymes, the SARS-CoV-2 main protease (M^pro) has been deemed a promising drug target vs. COVID-19. Indeed, M^pro is a pivotal enzyme for viral replication, and it is highly conserved within coronaviruses. It showed a high extent of conservation of the protease residues essential to the enzymatic activity, emphasizing its potential as a drug target to develop wide-spectrum antiviral agents effective not only vs. SARS-CoV-2 variants but also against other coronaviruses. Even though the FDA-approved drug nirmatrelvir, a M^pro inhibitor, has boosted the antiviral therapy for the treatment of COVID-19, the drug shows several drawbacks that hinder its clinical application. Herein, we report the synthesis of new thiazolidine-4-one derivatives endowed with inhibitory potencies in the micromolar range against SARS-CoV-2 M^pro. In silico studies shed light on the key structural requirements responsible for binding to highly conserved enzymatic residues, showing that the thiazolidinone core acts as a mimetic of the Gln amino acid of the natural substrate and the central role of the nitro-substituted aromatic portion in establishing π-π stacking interactions with the catalytic His-41 residue.

The human immunodeficiency virus (HIV) is the primary cause of acquired immune deficiency syndrome (AIDS), one of the deadliest pandemic diseases. Various mechanisms and procedures have been pursued to synthesise several anti-HIV agents, but due to the severe side effects and multidrug resistance spawning from the treatment of HIV/AIDS using highly active retroviral therapy (HAART), it has become imperative to design and synthesise novel anti-HIV agents. Literature has shown that natural sources, particularly the plant kingdom, can release important metabolites that have several biological, mechanistic and structural representations similar to chemically synthesised compounds. Certainly, compounds from natural and ethnomedicinal sources have proven to be effective in the management of HIV/AIDS with low toxicity, fewer side effects and affordability. From plants, fungi and bacteria, coumarin can be obtained, which is a secondary metabolite and is well known for its actions in different stages of the HIV replication cycle: protease, integrase and reverse transcriptase (RT) inhibition, cell membrane fusion and viral host attachment. These, among other reasons, are why coumarin moieties will be the basis of a good building block for the development of potent anti-HIV agents. This review aims to outline the synthetic pathways, structure–activity relationship (SAR) and POM analyses of coumarin hybrids with anti-HIV activity, detailing articles published between 2000 and 2023.