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
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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.
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新型 4-硝基咪唑类似物:合成、体外生物学评价、硅学研究和分子动力学模拟
合成了一系列新的 4-硝基咪唑芳基哌嗪 7-16、四唑 17 和 1,3,4-噻二唑 18 衍生物。筛选了所有衍生物对八种不同人类癌细胞株(Capan-1、HCT-116、LN229、NCI-H460、DND-41、HL-60、K562 和 Z138)的抗癌活性。事实证明,化合物 17 是该系列中最有效的化合物,它能抑制大多数所选人类癌细胞株的增殖,其 IC50 值在低微摩尔范围内。此外,化合物 11 对部分癌细胞株的 IC50 值为 8.60-64.0 μM。这些发现表明,衍生物 17 有可能成为进一步开发新型抗增殖剂的新先导化合物。此外,还对 17-18 进行了抗菌和抗结核活性评估。衍生物 17 和 18 是该系列中对金黄色葡萄球菌 Wichita 菌株和耐甲氧西林金黄色葡萄球菌(MRSA)菌株以及结核分枝杆菌 mc26230 菌株最有效的化合物。此外,还评估了 7-18 号化合物对多种病毒的抗病毒活性,但未发现任何活性。研究人员还对化合物 17 与急性髓性白血病中的假定蛋白靶点进行了对接研究。此外,还研究了 17 和 18 的分子动力学模拟。
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