Novel 4-nitroimidazole analogues: Synthesis, in vitro biological evaluation, in silico studies and molecular dynamics simulation

Abstract

Abstract A new series of 4-nitroimidazole bearing substituted aryl piperazines 7-16, tetrazole 17 and 1,3,4-thiadiazole 18 derivatives was designed and synthesized. All derivatives were screened for their anticancer activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562 and Z138). Compound 17 proved the most potent compound of the series inhibiting proliferation of most of the selected human cancer cell lines with IC50 values in the low micromolar range. In addition, compound 11 exhibited IC50 values ranging 8.60 to 64.0 μM against a selection of cancer cell lines, whereas compound 18 showed IC50 values varying between 8.25 and 43.55 μM against all the selected cancer cell lines, whereas. These findings suggest that derivative 17 can potentially be a new lead compound for further development of novel antiproliferative agents. Additionally, compounds 17-18 were assessed for their antibacterial and antituberculosis activity, where derivatives 17 and 18 were the most potent compounds of the series against both Staphylococcus aureus strain Wichita and a methicillin resistant strain of Staphylococcus aureus (MRSA), as well as against M. tuberculosis strain mc26230. The antiviral activity of compounds 7-18 was also evaluated but no activity was found against the selected viruses. The docking studies were conducted to predict the interaction of derivative 17 with putative protein targets in acute myeloid leukemia, specifically Fms-like tyrosine kinase-3 (FLT3). The results showed a docking score of -8.132 kcal/mol-1, indicating a strong binding affinity. Additionally, it was observed that derivative 17 exhibited favorable hydrophobic interactions with the active site of the tyrosine kinase-3. Furthermore, the analysis of the 200 ns molecular dynamics simulation results based on the best-docked complexes 17 and 18 with tyrosine kinase-3 receptor demonstrates stable interactions, and the complexes undergo the same conformational fluctuations. The average of the calculated binding free energy of complex 17 and 18 are -184.6 kJ/mol and -160.2 kJ/mol, respectively, and the result demonstrated that complex 17 promoted higher stability than complex 18 to the tyrosine kinase-3.