Biopolym. Cell. 2022; 38(1):26-36.
Bioorganic Chemistry
1-Cycloalkanecarbonyl-substituted thioureas and thiosemicarbazides as effective dihydrofolate reductase inhibitors with antibacterial activity
1Kholodniak O. V., 1Tniguer M., 1Nosulenko I. S., 1Kinichenko A. O., 1Kandybey K. I., 1Antypenko O. M., 1Kovalenko S. I.
  1. Zaporizhia State Medical University
    26, Mayakovsky avenue, Zaporizhzhia, Ukraine, 69035

Abstract

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)cycloalkanecarboxamides, as highly active antimicrobial agents against E. coli and S. 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)cycloalkylcarboxamides 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.
Keywords: N-(R-carbamothioyl)cycloalkylcarboxamides, dihydrofolate reductase, molecular docking, inhibitors, antibacterial activity, SAR analysis

References

[1] Raimondi M, Randazzo O, La Franca M, Barone G, Vignoni E, Rossi D, Collina S. DHFR inhibitors: reading the past for discovering novel anticancer agents. Molecules. 2019; 24(6):1140.
[2] Sharma M, Chauhan PMS. Dihydrofolate reductase as a therapeutic target for infectious diseases: opportunities and challenges. Future Med Chem. 2012; 4(10):1335-65.
[3] Gangjee A, Jain HD, Kurup S. Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I. AntiCancer Agents Med Chem. 2007; 7(5):524-42.
[4] Gangjee A, Jain H, Kurup S. Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part II. AntiCancer Agents Med Chem. 2008; 8(2):205-31.
[5] Wright DL, Anderson AC. Antifolate agents: a patent review (2006-2010). Expert Opin Ther Pat. 2011; 21(9):1293-308.
[6] Anderson AC, Wright DL. Antifolate agents: a patent review (2010-2013). Expert Opin Ther Pat. 2014; 24(6):687-97.
[7] Wyss PC, Gerber P, Hartman PG, Hubschwerlen CH, Marty L, Martin S. Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. J Med Chem. 2003; 46(12):2304-12.
[8] Patel RB, Welling PG. Clinical Pharmacokinetics of Co-trimoxazole (trimethoprim-sulphamethoxazole). Clin Pharmacokinet. 1980;5(5): 405-23.
[9] Schneider P, Hawser S, Islam K. Iclaprim, a novel diaminopyrimidine with potent activity on trimethoprim sensitive and resistant bacteria. Bioorg Med Chem Lett. 2003; 13(23):4217-21.
[10] Kholodniak O, Kovalenko S. Sudstituted acylthioureas and acylthiosemicarbazides: synthesis and diological activity (minireview). ScienceRise: Pharmaceut Sci, 2022; 2(36):56-71.
[11] Antypenko L, Meyer F, Kholodniak O, Sadykova Z, Jirásková T, Troianova A, Buhaiova V, Cao S, Kovalenko S, Garbe LA, Steffens KG. Novel acyl thiourea derivatives: synthesis, antifungal activity, gene toxicity, drug-like screening and molecular docking. Arch Pharm (Weinheim). 2018; 352(2):e1800275.
[12] Kholodniak OV, Kazunin MS, Meyer F, Kovalenko SI, Steffens KG. Novel N-cycloalkylcarbonyl-N-arylthioureas: synthesis, design, antifungal activity and gene toxicity. Chem Biodivers. 2020; 17(7):e2000212.
[13] Kholodniak OV, Stavytskyi VV, Kazunin MS, Bukhtiayrova NV, Berst GG, Belenichev IF, Kovalenko SI. Design, synthesis and anticonvulsant activity of new diacylthiosemicarbazides. Biopolym Cell. 2021; 37(2):125-42.
[14] Filman DJ, Bolin JT, Matthews DA, Kraut J. Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 Å resolution. II. Environment of bound NADPH and implications for catalysis. J Biol Chem. 1982; 257:(22):13663-62.
[15] Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010; 31(2):455-61.
[16] Wayne PA Performance standards for antimicrobial disk susceptibility tests, Approved Standard 9th Edition. 2006. 52 p.