Rational design of bis-indolylmethane-oxadiazole hybrids as inhibitors of thymidine phosphorylase

• Published in: Bioorganic and Medicinal Chemistry
• Main Author: Taha M.; Rashid U.; Imran S.; Ali M.
• Format: Article
• Language: English
• Published: Elsevier Ltd 2018
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85047556645&doi=10.1016%2fj.bmc.2018.05.046&partnerID=40&md5=b8b86a9c07b0efb47642c7184ed60518

Inhibition of Thymidine phosphorylase (TP) is continuously studied for the design and development of new drugs for the treatment of neoplastic diseases. As a part of our effort to identify TP inhibitors, we performed a structure-based virtual screening (SBVS) of our compound collection. Based on the insights gained from structures of virtual screening hits, a scaffold was designed using 1,3,4-oxadiazole as the basic structural feature and SAR studies were carried out for the optimization of this scaffold. Twenty-five novel bis-indole linked 1,3,4-oxadiazoles (7–31) were designed, synthesized and tested in vitro against E. coli TP (EcTP). Compound 7 emerged as potent TP inhibitor with an IC50 value of 3.50 ± 0.01 μM. Docking studies were carried out using GOLD software on thymidine phosphorylase from human (hTP) and E. coli (EcTP). Various hydrogen bonding, hydrophobic interactions, and π-π stacking were observed between designed molecules and the active site amino acid residues of the studied enzymes. © 2018 Elsevier Ltd