Towards Covid-19 TMPRSS2 enzyme inhibitors and antimicrobial agents: Synthesis, antimicrobial potency, molecular docking, and drug-likeness prediction of thiadiazole-triazole hybrids.

ABSTRACT

1,3,4-Thiadiazole analogues 3 and 4 were synthesised via the reaction of 1-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl)ethan-1one 2 with vanillin or thiophene-2-carboxaldhyde, respectively through chalcone reaction. Compounds 3 and 4 were submitted to react with thiosemicarbazide affording 5-(4­hydroxy-3-methoxyphenyl)-3-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (5) give 3-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl)-5-(thiophen-2-yl)-4,5 dihydro-1H-pyrazole-1-carbothioamide (6), respectively. The letters were reacted with N-(4-chlorophenyl)-2-oxopropanehydrazonoyl chloride to give compounds 7 and 8. The chemical compositions of the novel compounds were affirmed by spectral and microanalytical data. Meanwhile, all the newly synthesized compounds have been screened for their ability to prevent the proliferation of different pathogens named Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, and Candida albicans in vitro. Additionally, the potency of the newly synthesized compounds to be anti-COVID-19 candidates was studied through a molecular docking study. The newly prepared molecules 2-8 were studied in silico against transmembrane serine protease 2 (TMPRSS2) to identify their potential therapeutic activity against Coronavirus. Moreover, the drug-likeness of the compounds was tested theoretically by ADMET studies. Compound 8 exhibited a better binding affinity (-9.1 kcal/mol) against the target enzyme TMPRSS2. Additionally, it respects Lipinski's rule of five and has acceptable ADMET properties, indicating that compound 8 could be interesting for the treatment of Covid-19.