The sudden outburst of Coronavirus disease (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses a massive threat to global public health. Currently, no therapeutic drug or vaccine exists to treat COVID-19. Due to the time taking process of new drug development, drug repurposing might be the only viable solution to tackle COVID-19. RNA‐dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication and hence, is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols effectively inhibit the RdRp of other RNA viruses. More importantly, polyphenols have been used as dietary supplementations for a long time and played beneficial roles in immune homeostasis. We were curious to study the binding of polyphenols with SARS-CoV-2 RdRp and assess their potential to treat COVID-19. Herein, we made a library of polyphenols that have shown substantial therapeutic effects against various diseases. They were successfully docked in the catalytic pocket of RdRp. The investigation reveals that EGCG, theaflavin (TF1), theaflavin-3’-O-gallate (TF2a), theaflavin-3’-gallate (TF2b), theaflavin 3,3'-digallate (TF3), hesperidin, quercetagetin, and myricetin strongly bind to the active site of RdRp. Further, a 150-ns molecular dynamic simulation revealed that EGCG, TF2a, TF2b, TF3 result in highly stable bound conformations with RdRp. The binding free energy components calculated by the MM-PBSA also confirm the stability of the complexes. We also performed a detailed analysis of ADME prediction, toxicity prediction, and target analysis for their druggability. Overall, our results suggest that EGCG, TF2a, TF2b, TF3 can inhibit RdRp and represent an effective therapy for COVID-19. Communicated by Ramaswamy H. Sarma

Natural products have been a bedrock for drug discovery for decades. (−)-Epigallocatechin-3-gallate (EGCG) is one of the widely studied natural polyphenolic compounds derived from green tea. It is the key component believed to be responsible for the medicinal value of green tea. Significant studies implemented in in vitro, in cellulo, and in vivo models have suggested its anti-oxidant, anti-cancer, anti-diabetic, anti-inflammatory, anti-microbial, neuroprotective activities etc. Despite having such a wide array of therapeutic potential and promising results in preclinical studies, its applicability to humans has encountered with rather limited success largely due to the poor bioavailability, poor membrane permeability, rapid metabolic clearance and lack of stability of EGCG. Therefore, novel techniques are warranted to address those limitations so that EGCG or its modified analogs can be used in the clinical setup. This review comprehensively covers different strategies such as structural modifications, nano-carriers as efficient drug delivery systems, synergistic studies with other bioactivities to improve the chemico-biological aspects (e.g., stability, bioavailability, permeability, etc.) of EGCG for its enhanced pharmacokinetics and pharmacological properties, eventually enhancing its therapeutic potentials. We think this review article will serve as a strong platform with comprehensive literature on the development of novel techniques to improve the bioavailability of EGCG so that it can be translated to the clinical applications.

Drug-resistant bacterial infections impose a major threat to human health, as current antibiotic treatments are becoming increasingly ineffective. Priority has been given to the development of alternative medications to curb the development of resistance or agents that can work on the resistance strains. Among various promising approaches, 1,2,3-triazole-based molecular hybrids have emerged as excellent candidates owing to their ease of synthesis, high structural diversity, functional tunability, and biocompatibility. The rapid advancement of biological understanding of 1,2,3-triazole has been greatly aided by the discovery of the Click reaction. Drugs with a single molecular target often fail to kill the bacteria effectively, and even if they do, the bacteria eventually become resistant by virtue of mutations or other mechanisms. In this context, the 1,2,3-triazole group has been explored to design novel molecular hybrids to combat antimicrobial resistance in an effective manner. Different types of 1,2,3-triazole-based hybrids have been developed that have shown inhibitory effects on critical bacterial enzymes, the ability to produce intracellular reactive oxygen species, and the ability to disrupt the cell membrane. Herein, we discuss the strategic design principles of triazole-based hybrids, their antibacterial potential, especially focusing on the drug resistance issue, and future perspectives to critically assess their potential for multitargeting antibacterial agents. The presented information can lead to the development of novel multifaceted antibacterial agents in the future by means of their unique chemical features to address the growing challenge of drug resistance.

Among the synthesized 4′′-alkyl EGCG derivatives, 4′′-C ₁₄ EGCG inhibited EGF stimulated phosphorylation of EGFR and its downstream signaling pathways, ERK and Akt. 4′′-C ₁₄ EGCG showed significantly improved stability than EGCG and induced apoptosis.