Novel pyrazole-biphenyl carboxamides showed dual antimicrobial and SARS-CoV2 entry-level inhibition activity potentials. The antimicrobial activity was broad-spectrum and the in-silico SARS-CoV2 spike protein, a main causative agent of COVID-19, was found to restrict its entry-level interaction with human Angiotensin Converting Enzyme (hACE). Thus, these novel molecules could have been the future drugs to treat both microbial and viral infections.

Abstract

Microbial diseases including viral infection are big issues globally. Effective medicinal discovery for them is the need for the day. In this study, we report pyrazole-biphenyl-carboxamides (4a-l) validated for their SARS-CoV2 entry-level restriction effect over studying the protein–protein interaction of SARS-CoV2 with human ACE protein. Their extended antimicrobial properties were also evaluated. Online and offline software tools predicted MD simulation and ADMET druggability in silico. The antimicrobial efficacy of all compounds was also evaluated against Gram+^ve Streptococcus pneumoniae (MTCC 1936), Staphylococcus aureus (MTCC 737) and Gram-^ve Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424) (bacteria). In the results, compounds 4g and 4i were evenly active against both bacteria at a low concentration range (MIC: 1.00 to 9.5 μg/mL) and displayed lesser toxicity to tested mammalian cells (EC₁₀₀ = 75 μg/mL). Furthermore, it was able to kill metabolically inactive bacterial cells and eradicate established biofilms of Methicillin-resistant Staphylococcus aureus (MRSA). Both the compounds inhibited DNA gyrase well with an IC₅₀ 0.25 μM (96% relative activity) and 0.52 μM (97% relative activity) respectively. Compounds (4a-l) showed restrictive efficiency of SARS-CoV2 spike protein (SC2SP) and human angiotensin-converting enzyme 2 (hACE2) entry-level association in COVID-19 in silico. To assess this ability, firstly, we identified the crucial amino acid residues involved in the interface of SARS-CoV-2 and hACE2 virtually. We recognized the ability of 4a-l binding to the binding interface to SARS-CoV2; thus, the interaction of SC2SP-hACE2 was effectively inhibited.