Design and synthesis of novel thiadiazole-thiazolone hybrids as potential inhibitors of the human mitotic kinesin Eg5
| Autor: | Chuin Lean Tham, Samukelisiwe Pretty Khathi, Balakumar Chandrasekaran, Sivanandhan Karunanidhi, Rajshekhar Karpoormath, Nisar Sayyad, Frank Kozielski |
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| Rok vydání: | 2018 |
| Předmět: |
Stereochemistry
In silico Clinical Biochemistry Pharmaceutical Science Kinesins 01 natural sciences Biochemistry Microtubules 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Microtubule Drug Discovery Thiadiazoles Molecule Humans Molecular Biology IC50 ADME Adenosine Triphosphatases Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry In vitro 0104 chemical sciences Thiazoles 030220 oncology & carcinogenesis Drug Design Lipinski's rule of five Molecular Medicine Kinesin |
| Zdroj: | Bioorganicmedicinal chemistry letters. 28(17) |
| ISSN: | 1464-3405 |
| Popis: | A novel series of 1,3,4-thiadiazole-thiazolone hybrids 5a–v were designed, synthesized, characterized, and evaluated against the basal and the microtubule (MT)-stimulated ATPase activity of Eg5. From the evaluated derivatives, 5h displayed the highest inhibition with an IC50 value of 13.2 µM against the MT-stimulated Eg5 ATPase activity. Similarly, compounds 5f and 5i also presented encouraging inhibition with IC50 of 17.2 µM and 20.2 µM, respectively. A brief structure–activity relationship (SAR) analysis indicated that 2-chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to enzyme inhibition. An in silico molecular docking study using the crystal structure of Eg5 further supported the SAR and reasoned the importance of crucial molecular protein–ligand interactions in influencing the inhibition of the ATPase activity of Eg5. The magnitude of the electron-withdrawing functionalities over the hybrids and the critical molecular interactions contributed towards higher in vitro potency of the compounds. The drug-like properties of the synthesized compounds 5a–v were also calculated based on the Lipinski’s rule of five and in silico computation of key pharmacokinetic parameters (ADME). Thus, the present work unveils these hybrid molecules as novel Eg5 inhibitors with promising drug-like properties for future development. |
| Databáze: | OpenAIRE |
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