Synthesis, Characterisation and Molecular Docking Studies of Bioactive Thiazoles as Promising Antibacterial Agents

Chang, Wei Jin (2025) Synthesis, Characterisation and Molecular Docking Studies of Bioactive Thiazoles as Promising Antibacterial Agents. Masters thesis, Tunku Abdul Rahman University of Management and Technology.

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Abstract

Antimicrobial resistance in bacteria is developing in hospital and community settings which drastically reduces the effectiveness of treatment with existing antibiotics. In this study, thiazole compounds 4a – e and 5a – e were synthesized, characterized and evaluated for their antibacterial activity, followed by in silico studies. The thiazole esters 4a – e were synthesized from Hantzsch cyclization reaction from thioamides 2a – e and bromoketone 3 and hydrolysed to afford thiazole carboxylic acids 5a – e, all of which were characterized using spectroscopic methods, such as 1H and 13C nuclear magnetic resonance spectroscopy (NMR), Fourier-Transform Infrared Spectroscopy (FTIR) and Liquid Chromatography coupled to Mass Spectrometry (LC-MS). The thiazole compounds 4a – e and 5a – e were evaluated for their antibacterial activity using disc diffusion test, agar dilution test and broth microdilution test on Gram-positive bacteria (Staphylococcus aureus, Bacillus cereus) and Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii). The thiazole compounds were then studied using molecular docking with Autodock 4 and Protein Plus to evaluate their binding with 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR, PDB code: 1Q0Q), followed by pharmacokinetics study using SwissADME. The thiazole esters 4a – e were synthesized in good yields of 74 – 96%, and hydrolysed to thiazole carboxylic acids 5a – e with 38% to quantitative yield. The electron density on the thiazole scaffold was varied by selecting the appropriate electron-donating and electron-withdrawing groups on the phenyl ring, and testing the analogues carrying these substituents with respect to antibacterial activity. Thiazoles 4a, 4e, and 5d were found to have activity against Gram-positive and Gram-negative bacteria. Thiazole 4a inhibited a broad spectrum of bacteria (S. aureus, E. coli, A. baumannii) at MIC 512 μg/mL and K. pneumoniae at MIC 256 μg/mL. Structure-activity relationship shows that an unoccupied para position at phenyl group of thiazole 4 and an electron-withdrawing nitro substituent on thiazole 5 are important features for activity. Molecular docking of thiazole compounds 4a – e and 5a – e predicted binding energy with DXR enzyme in the range of -6.37 to -7.90 kcal/mol. In silico pharmacokinetics study showed that thiazole compounds 4a – e and 5a – e have high oral bioavailability and thiazoles 4a, c, e were able to cross the blood-brain barrier. The new thiazoles 4a – e and 5a – e will aid in the development of new antibiotics against these bacteria, which aligns with UNESCO’s Good Health and Well-Being Goals (SDG #3) by improving treatment of harmful diseases in the human population. Keywords: Thiazoles, thioamides, Hantzsch cyclization, antibacterial, molecular docking.