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

Tuberculosis remains a serious killer among infectious diseases due to its incidence, mortality, and occurrence of resistant mycobacterial strains. The challenge to discover new antimycobacterial agents forced us to prepare a series of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides 1-19 via the acylation of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol with various activated (hetero)arylcarboxylic acids. These novel compounds have been tested in vitro against a panel of clinically important fungi and bacteria, including mycobacteria. Some of the compounds inhibited the growth of mycobacteria in the range of micromolar concentrations and retained this activity also against multidrug-resistant clinical isolates. Half the maximal inhibitory concentrations against the HepG2 cell line indicated an acceptable toxicological profile. No growth inhibition of other bacteria and fungi demonstrated selectivity of the compounds against mycobacteria. The structure-activity relationships have been derived and supported with a molecular docking study, which confirmed a selectivity toward the potential target leucyl-tRNA synthetase without an impact on the human enzyme. The presented compounds can become important materials in antimycobacterial research.

• Keywords
• antimicrobial, antimycobacterial, benzoxaborole, cytotoxicity, molecular docking, multidrug-resistant tuberculosis, tuberculosis,
• MeSH
• Amides chemistry   pharmacology   MeSH
• Amino Acyl-tRNA Synthetases * MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• Anti-Infective Agents * pharmacology   MeSH
• Antitubercular Agents pharmacology   MeSH
• Fungi MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium tuberculosis * MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amides MeSH
• Amino Acyl-tRNA Synthetases * MeSH
• Anti-Bacterial Agents MeSH
• Anti-Infective Agents * MeSH
• Antitubercular Agents MeSH

Antimicrobial drug resistance is currently one of the most critical health issues. Pathogens resistant to last-resort antibiotics are increasing, and very few effective antibacterial agents have been introduced in recent years. The promising drug candidates are often discontinued in the primary stages of the drug discovery pipeline due to their unspecific reactivity (PAINS), toxicity, insufficient stability, or low water solubility. In this work, we investigated a series of substituted N-oxazolyl- and N-thiazolylcarboxamides of various pyridinecarboxylic acids. Final compounds were tested against several microbial species. In general, oxazole-containing compounds showed high activity against mycobacteria, especially Mycobacterium tuberculosis (best MICH37Ra = 3.13 µg/mL), including the multidrug-resistant strains. Promising activities against various bacterial and fungal strains were also observed. None of the compounds was significantly cytotoxic against the HepG2 cell line. Experimental measurement of lipophilicity parameter log k'w and water solubility (log S) confirmed significantly (typically two orders in logarithmic scale) increased hydrophilicity/water solubility of oxazole derivatives in comparison with their thiazole isosteres. Mycobacterial β-ketoacyl-acyl carrier protein synthase III (FabH) was suggested as a probable target by molecular docking and molecular dynamics simulations.

• Keywords
• aminooxazole, aminothiazole, antimycobacterial activity, docking, isostere, molecular docking, molecular dynamics, pyridine, water solubility,
• Publication type
• Journal Article MeSH