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Growing Science » Current Chemistry Letters » Thiopental-Inspired alkylpyrimidines as dual-target antimicrobial agents: Synthesis, biological activity, and molecular docking validation

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Current Chemistry Letters

ISSN 1927-730x (Online) - ISSN 1927-7296 (Print)
Quarterly Publication
Volume 14 Issue 4 pp. 831-842 , 2025

Thiopental-Inspired alkylpyrimidines as dual-target antimicrobial agents: Synthesis, biological activity, and molecular docking validation Pages 831-842 Right click to download the paper Download PDF

Authors: Mahmoud M. Hamed, Mostafa Ahmed, Adel M. Kamal El-Dean, M. Yasser Alsedfy, Mahmoud S. Tolba

DOI: 10.5267/j.ccl.2025.8.001

Keywords: Thiopental derivatives, Antimicrobial agents, Pyrimidine hybrids, Molecular docking, Structure-activity relationships (SARs), CYP51 inhibition

Abstract: Alkylpyrimidine derivatives, particularly thiopental-based analogs, have emerged as promising scaffolds for antimicrobial drug development. In this study, we designed and synthesized a series of novel thiopental-pyrimidine hybrids (3a–c, 4) through efficient condensation reactions, and characterized these compounds by using NMR, IR, and mass spectrometry. Antimicrobial screening revealed significant activity against clinically relevant strains: derivative 3a exhibited selective inhibition of Bacillus subtilis (MIC: 10.5±0.4 mg/mL) and Escherichia coli (MIC: 22.1±0.3 mg/mL), while 3c showed potent antifungal effects against Candida albicans (MIC: 11.6±0.4 mg/mL). Molecular docking studies elucidated the mechanistic basis of this activity, with 3a binding to penicillin-binding protein (PBP; −6.4 kcal/mol) via hydrogen bonds (SER392) and hydrophobic interactions (TYR430, PRO660), and 3c coordinating with the heme iron of CYP51 (−7.8 kcal/mol) akin to fluconazole. Notably, 3c thioether linkage facilitated π-cation/anion interactions with PHE463, rationalizing its antifungal specificity. Structure-activity relationships (SAR) underscored the critical roles of electron-deficient pyrimidine cores for antibacterial activity and sulfur moieties for antifungal action. These findings position thiopental-pyrimidine hybrids as versatile leads for combating microbial resistance, with 3c representing a particularly promising antifungal candidate. Our integrated synthetic, biological, and computational approach provides a blueprint for optimizing these scaffolds for clinical translation.

How to cite this paper
Hamed, M., Ahmed, M., El-Dean, A., Alsedfy, M & Tolba, M. (2025). Thiopental-Inspired alkylpyrimidines as dual-target antimicrobial agents: Synthesis, biological activity, and molecular docking validation.Current Chemistry Letters, 14(4), 831-842.

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Journal: Current Chemistry Letters | Year: 2025 | Volume: 14 | Issue: 4 | Views: 258 | Reviews: 0

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