Design, Synthesis, Neuroprotective and Antibacterial Activities of 1,2,4‐Triazolo[3,4‐b]1,3,4‐thiadiazole Linked Thieno[2,3‐d]pyrimidine Derivatives and In Silico Docking Studies

• Published in: ChemistrySelect (Weinheim) Vol. 4; no. 5; pp. 1627 - 1634
• Main Authors: Settypalli, Triloknadh, Chunduri, Venkata Rao, Kerru, Nagaraju, Nallapaneni, Hari Krishna, Chintha, Venkata Ramaiah, Daggupati, Trinath, Yeguvapalli, Suneetha, Wudayagiri, Rajendra
• Format: Journal Article
• Language: English
• Published: 07-02-2019
• Subjects: Antibacterial activity; Docking studies; Neuroprotectivity; Neurotoxicity
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.201803917

In pursuit of neuroprotective and antimicrobial agents, a series of 1,2,4‐triazolo[3,4‐b]1,3,4‐thiadiazole incorporated thieno[2,3‐d]pyrimidine derivatives 10 a‐l has been designed, synthesized. The final target compounds were screened for neuroprotective, neurotoxic and antibacterial activities. The compounds derived from 4‐methylphenyl (10 a) and 4‐nitrophenyl (10 c) have showed good neuroprotective activity against H2O2 induced PC12 cell death at respective EC50 values of 10.44, 14.12 μg/mL. However 10 b and 10 k showed superior neurotoxic effects than rest of the compounds with respective CC50 values of 100.16, 120 μg/mL. Potent antibacterial activity was shown by 10 f (R=‐Me, R2=‐OMe), 10 h (R=‐Me, R2=‐Cl) against the four bacterial pathogens such as S.aureus, B.subtilis, E.coli and P.aeruginosa at low minimum inhibitory concentration (MIC) range. Further, in silico docking studies were performed for all the synthesized compounds with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC bacterial proteins. Interestingly, 10 f, 10 h showed good binding affinities with target proteins and these results are in good compliance with the in vitro activity profile data.
Novel 1,2,4‐triazolo[3,4‐b]1,3,4‐thiadiazole incorporated thieno[2,3‐d]pyrimidine derivatives 10 a‐l have been designed, synthesized and screened for neuroprotective, neurotoxic and antibacterial activities. Compounds 10 a (N‐(4‐Methoxyphenyl)‐5‐methyl‐6‐(3‐(p‐tolyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐6‐yl)thieno[2,3‐d]pyrimidin‐4‐amine), 10 c (N‐(4‐Methoxyphenyl)‐5‐methyl‐6‐(3‐(4‐nitrophenyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐6‐yl)thieno[2,3‐d]pyrimidin‐4‐amine) have exhibited good neuroprotective activity whereas 10 b, 10 k showed superior neurotoxic effects on the PC12 cells. Further, compounds 10 f (R=‐Me, R2=‐OMe), 10 h (R=‐Me, R2=‐Cl) had been identified as potent antibacterials when compared with gentamicin. Molecular docking study of all target compounds was also performed with selected bacterial proteins.