Design and synthesis of novel thiadiazole-thiazolone hybrids as potential inhibitors of the human mitotic kinesin Eg5. Issue 17 (15th September 2018)

• Record Type: Journal Article
• Authors: Khathi, Samukelisiwe Pretty; Chandrasekaran, Balakumar; Karunanidhi, Sivanandhan; Tham, Chuin Lean; Kozielski, Frank; Sayyad, Nisar; Karpoormath, Rajshekhar
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 17(2018)
• Page Start: 2930
• Page End: 2938
• Publication Date: 2018-09-15
• Subjects: 1, 3, 4-Thiadiazole-thiazolone -- MT-stimulated ATPase of Eg5 -- Hybridization -- Knoevenagel condensation -- GLIDE -- ADME prediction; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.07.007
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Novel 1, 3, 4-thiadiazole-thiazolone hybrids (5a –v ) were designed and synthesized. 5f, 5 h and 5i showed promising inhibition of MT-stimulated Eg5 ATPase activity. In silico molecular docking supported the SAR studies. The Lipinski's rule of five and ADME validated the drug-likeness of the hybrids. Abstract: 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.