Infectious diseases, including bacterial, fungal, and viral, have once again gained urgency in the drug development pipeline after the recent COVID-19 pandemic. Tuberculosis (TB) is an old infectious disease for which eradication has not yet been successful. Novel agents are required to have potential activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB. In this study, we present a series of 2-phenyl-N-(pyridin-2-yl)acetamides in an attempt to investigate their possible antimycobacterial activity, cytotoxicity on the HepG2 liver cancer cell line, and-as complementary testing-their antibacterial and antifungal properties against a panel of clinically important pathogens. This screening resulted in one compound with promising antimycobacterial activity-compound 12, MICMtb H37Ra = 15.625 μg/mL (56.26 μM). Compounds 17, 24, and 26 were further screened for their antiproliferative activity against human epithelial kidney cancer cell line A498, human prostate cancer cell line PC-3, and human glioblastoma cell line U-87MG, where they were found to possess interesting activity worth further exploration in the future.

• Keywords
• antibacterial, antimycobacterial, antiproliferative, drug design, pyridine, tuberculosis,
• MeSH
• Acetamides * chemistry   pharmacology   MeSH
• Antifungal Agents pharmacology   chemistry   chemical synthesis   MeSH
• Antitubercular Agents pharmacology   chemistry   MeSH
• Hep G2 Cells MeSH
• Humans MeSH
• Microbial Sensitivity Tests * MeSH
• Mycobacterium tuberculosis * drug effects   MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation * drug effects   MeSH
• Antineoplastic Agents pharmacology   chemistry   MeSH
• Pyridines chemistry   pharmacology   MeSH
• SARS-CoV-2 drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetamides * MeSH
• Antifungal Agents MeSH
• Antitubercular Agents MeSH
• Antineoplastic Agents MeSH
• Pyridines MeSH

We prepared a series of substituted N-(pyrazin-2-yl)benzenesulfonamides as an attempt to investigate the effect of different linkers connecting pyrazine to benzene cores on antimicrobial activity when compared to our previous compounds of amide or retro-amide linker type. Only two compounds, 4-amino-N-(pyrazin-2-yl)benzenesulfonamide (MIC = 6.25 μg/mL, 25 μM) and 4-amino-N-(6-chloropyrazin-2-yl)benzenesulfonamide (MIC = 6.25 μg/mL, 22 μM) exerted good antitubercular activity against M. tuberculosis H37Rv. However, they were excluded from the comparison as they-unlike the other compounds-possessed the pharmacophore for the inhibition of folate pathway, which was proven by docking studies. We performed target fishing, where we identified matrix metalloproteinase-8 as a promising target for our title compounds that is worth future exploration.

• Keywords
• Mycobacterium tuberculosis, anti-infectives, pyrazinamide, sulfonamide, target fishing,
• MeSH
• Anti-Infective Agents chemical synthesis   chemistry   pharmacology   MeSH
• Antitubercular Agents chemical synthesis   chemistry   pharmacology   MeSH
• Benzenesulfonamides MeSH
• Chemical Phenomena MeSH
• Microbial Sensitivity Tests MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Sulfonamides chemical synthesis   chemistry   pharmacology   MeSH
• Chemistry Techniques, Synthetic MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Infective Agents MeSH
• Antitubercular Agents MeSH
• Sulfonamides MeSH