Synthesis of new methylthiourea-thiophene, -thiazole, and -pyrazole conjugates: Molecular modelling and docking studies as antimicrobial agents.

• New methylthiourea-thiophene, -thiazole, or -pyrazole conjugates were synthesized and characterized. • DFT calculations disclosed that synthesized derivatives were nonplanar. • The resulted FMO's energies indicated that all the hybrids have little energy gap. • In-depth molecular docking was explored against the bacterial protein PDB ID 1AJ6. • Methylthiourea-conjugates may exhibit interaction owing to CYP450 isoform inhibition. A series of new functionalized thiophene, thiazole, and pyrazole conjugates with methylthiourea was synthesized by cyclization of 1-(4-(2-bromoacetyl)phenyl)-3-methylthiourea (1) with different thioacetanilides, aryl carbamodithioates, and hydrazonoyl cyanide reagents, respectively. The DFT/B3LYP method showed that the thiazole derivatives 5a–c had lower HOMO-LUMO energies and ΔE H-L than the thiophenes 3a–c and the pyrazoles 7a–c. The synthesized conjugates were examined to investigate their potential as antibacterial agents. Analogue 3a was found to be extremely effective against Gram-positive bacteria by rigorous biological screening, while analogues 3c and 7a were found to be effective against Gram-negative bacteria. Antifungal tests revealed that analogues 3c and 5b were very effective. Molecular docking studies of the bacterial protein PDB ID 1AJ6 showed that analogues 3b and 7b bind most strongly. This suggests that they have important interactions through hydrogen bonds and π-interactions that keep the ligand-receptor complex together. Interestingly, analogue 7b not only demonstrated the highest binding affinity but also excellent structural compatibility with the protein target, establishing it as a lead molecule for further investigation. Despite their promising pharmacological qualities, all analogues faced pharmacokinetic challenges such as poor gastrointestinal absorption and blood-brain barrier permeability. Analogue 3c , for instance, demonstrated a balance between lipophilicity and a lower Topological polar surface area (TPSA) value (113.49 Ų) that supports good gastrointestinal absorption while having poor projected bioavailability, according to Swiss-ADME. [ABSTRACT FROM AUTHOR]