Distinct Mechanisms of Cytotoxicity in Novel Nitrogenous Heterocycles: Future Directions for a New Anti-Cancer Agent |
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| Authors: | Rasha Saad Suliman Sahar Saleh Alghamdi Rizwan Ali Ishrat Rahman Tariq Alqahtani Ibrahim K Frah Dimah A Aljatli Sarah Huwaizi Shatha Algheribe Zeyad Alehaideb Imadul Islam |
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| Institution: | 1.College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh 14611, Saudi Arabia; (R.A.); (T.A.); (I.K.F.); (D.A.A.);2.Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs, Riyadh 14811, Saudi Arabia; (S.H.); (S.A.); (Z.A.); (I.I.);3.Department of Basic Dental Sciences, College of Dentistry, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia; |
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| Abstract: | Electron-rich, nitrogenous heteroaromatic compounds interact more with biological/cellular components than their non-nitrogenous counterparts. The strong intermolecular interactions with proteins, enzymes, and receptors confer significant biological and therapeutic properties to the imidazole derivatives, giving rise to a well-known and extensively used range of therapeutic drugs used for infections, inflammation, and cancer, to name a few. The current study investigates the anti-cancer properties of fourteen previously synthesized nitrogenous heterocycles, derivatives of imidazole and oxazolone, on a panel of cancer cell lines and, in addition, predicts the molecular interactions, pharmacokinetic and safety profiles of these compounds. Method: The MTT and CellTiter-Glo® assays were used to screen the imidazole and oxazolone derivatives on six cancer cell lines: HL60, MDA-MB-321, KAIMRC1, KMIRC2, MCF-10A, and HCT8. Subsequently, in vitro tubulin staining and imaging were performed, and the level of apoptosis was measured using the Promega ApoTox-Glo® triplex assay. Furthermore, several computational tools were utilized to investigate the pharmacokinetics and safety profile, including PASS Online, SEA Search, the QikProp tool, SwissADME, ProTox-II, and an in silico molecular docking study on tubulin to identify the critical molecular interactions. Results: In vitro analysis identified compounds 8 and 9 to possess the most significant potent cytotoxic activity on the HL60 and MDA-MB-231 cell lines, supported by PASS Online anti-cancer predictions with pa scores of 0.413 and 0.434, respectively. In addition, compound 9 induced caspase 3/7 dependent-apoptosis and interfered with tubulin polymerization in the MDA-MB-231 cell line, consistent with in silico docking results, identifying binding similarity to the native ligand colchicine. All the derivatives, including compounds 8 and 9, had acceptable pharmacokinetics; however, the safety profile was suboptimal for all the tested derivates except compound 4. Conclusion: The imidazole derivative compound 9 is a promising anti-cancer agent that switches on caspase-dependent apoptotic cell death and modulates microtubule function. Therefore, it could be a lead compound for further drug optimization and development. |
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| Keywords: | Imidazole oxazolone ADME target prediction anti-cancer tubulin inhibitors |
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