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

Yaseen A Al-Soud; Sondos O Al-Sawakhnah; Raed A Al-Qawasmeh; Najim A Al-Masoudi; Ala'a H Al-Ahmad; Lamiaa Al-Maliki; Lasse van Geelen; Rainer Kalscheuer; Bahjat A Saeed; Amneh Shtaiwi; Holger Stark

doi:10.1515/znc-2023-0146

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

Z Naturforsch C J Biosci. 2024 Apr 8. doi: 10.1515/znc-2023-0146. Online ahead of print.

Affiliations

¹ Department of Chemistry, College of Science, University of Al al-Bayt, Al-Mafraq, Jordan.
² Department of Chemistry, Pure and Applied Chemistry Group, College of Science, University of Sharjah, Sharjah 27272, UAE.
³ Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq.
⁴ Department of Molecular and Medical Biotechnology, Al-Nahrain University, Baghdad, Iraq.
⁵ Institute of Pharmaceutical Biology and Biotechnology, Heinrich - Heine - University Düsseldorf, Duesseldorf 40225, Germany.
⁶ Department of Chemistry, College of Education for Pure Science, University of Basrah, Basrah, Iraq.
⁷ Faculty of Pharmacy, Middle East University, Queen Alia Airport Street, 11610, Amman, Jordan.
⁸ Institute of Pharmaceutical and Medicinal Chemistry, Heinrich - Heine - University Düsseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany.

PMID: 38578162
DOI: 10.1515/znc-2023-0146

Abstract

A new series of 4-nitroimidazole bearing aryl piperazines 7-16, tetrazole 17 and 1,3,4-thiadiazole 18 derivatives was 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 8.60-64.0 μM against a selection of cancer cell lines. These findings suggest that derivative 17 can potentially be a new lead compound for further development of novel antiproliferative agents. Additionally, 17-18 were assessed for their antibacterial and antituberculosis activity. Derivatives 17 and 18 were the most potent compounds of this series against both Staphylococcus aureus strain Wichita and a methicillin resistant strain of S. aureus (MRSA), as well as against Mycobacterium tuberculosis strain mc²6230. The antiviral activity of 7-18 was also evaluated against diverse viruses, but no activity was detected. The docking study of compound 17 with putative protein targets in acute myeloid leukemia had been studied. Furthermore, the molecular dynamics simulation of 17 and 18 had been investigated.

Keywords: 4-nitroimidazoles; biological activity; cytotoxicity; docking study; molecular dynamics simulation.