1-Cycloalkanecarbonyl-substituted thioureas and thiosemicarbazides as effective dihydrofolate reductase inhibitors with antibacterial activity

Aim. Search for new antibacterial agents with dihydrofolate reductase-inhibitory activity among N -(R-carbamothiol)cycloalkylcarboxamides using in silico and in vitro methodology, SAR analysis to optimize the synthesis of new potential antinicrobials. Methods. Molecular docking, in vitro DHFR inhibition assay, antimicrobial evaluation, SAR analysis, statistical methods. Results. According to the results of molecular docking to the active center of dihydrofolate reductase (DHFR), namely affinity, the main types of interactions and arrangement in the active center of the enzyme, several N -(R-carbamothioyl)cycloalkylcarboxamides were selected for their inhibitory effect. Based on in vitro screening, few promising compounds with high ability to inhibit DHFR were identified. It was found, that diacylsemicarbazides are more effective inhibitors of DHFR compared to acylthioureas. The studies on antibacterial activity have revealed several promising compounds, namely N -(2-R-hydrazine-1-carbonothioyl)cy-cloalkanecarboxamides, as highly active antimicrobial agents against E. сoli and St. aureus (MIC 3.125–25.0 μg/ml) with high DHFR-inhibitory effect, the activity of which competes with the comparison drug “Nitrofurazone”. This justifies the continuation of systematic research in this direction. Conclusions. A well-founded search among N -(R-carbamothiol)cycloalkyl-carboxamides for new antibacterial agents with dihydrofolate reductase-inhibitory activity, using in silico and in vitro methodology, established relationship between the chemical structure and activity aimed at further design of new potential drug agents.