Design and Development of Small-Molecule Arylaldoxime/5-Nitroimidazole Hybrids as Potent Inhibitors of MARK4: a Promising Approach for Target-Based Cancer Therapy
| Autor: | Imtaiyaz Hassan, Amir Azam, Fernando Avecilla, Shadab Miyan Siddiqui, Nashrah Sharif Khan, Parvez Khan, Mudasir Nabi Peerzada |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | ACS Omega, Vol 5, Iss 36, Pp 22759-22771 (2020) RUC. Repositorio da Universidade da Coruña Universitat Oberta de Catalunya (UOC) RUC: Repositorio da Universidade da Coruña Universidade da Coruña (UDC) ACS Omega |
| Popis: | [Abstract] Microtubule affinity-regulating kinase 4 (MARK4), a member of the serine/threonine kinase family, is an emerging therapeutic target in anticancer drug discovery paradigm due to its involvement in regulation of microtubule dynamics, cell cycle regulation, and cancer progression. Therefore, to identify the novel chemical architecture for the design and development of novel MARK4 inhibitors with concomitant radical scavenging property, a series of small-molecule arylaldoxime/5-nitroimidazole conjugates were designed and synthesized via multistep chemical reactions following the pharmacophoric hybridization approach. Compound 4h was identified as a promising MARK4 inhibitor with high selectivity toward MARK4 inhibition as compared to the panel of screened 30 kinases pertaining to the serine/threonine family, which was validated by molecular docking and fluorescence binding studies. The comprehensive cell-based examination divulged the promising apoptotic, antiproliferative, and antioxidant potential for the chemotype 4h. The compound 4h was endowed with the Ka value of 3.6 × 103 M–1 for human serum albumin, which reflects its remarkable transportation and delivery properties to the target site via blood. The present study impedes that in the future, such compounds may stand as optimized pharmacological lead candidates in drug discovery for targeting cancer via MARK4 inhibition with a remarkable anticancer profile. Council of Scientific and Industrial Research (India); 09/466 (0220) 2K19 EMR-I Government of India; EMR/2015/002372 Government of India; BT/PR12828/AAQ/1/622/2015 Indian Council of Medical Research; 45/9/2019-PHA/BMS |
| Databáze: | OpenAIRE |
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