Synthesis, In Silico Molecular Docking, ADME Evaluation and In Vitro Antiplasmodial Activity of Pyrimidine‐Based Hybrid Molecules. Issue 43 (26th November 2019)

• Record Type: Journal Article
• Authors: Chopra, Rakesh; Singh, Lovepreet; Chibale, Kelly; Singh, Kamaljit
• Is Part Of: ChemistrySelect. Volume 4:Issue 43(2019)
• Page Start: 12556
• Page End: 12561
• Publication Date: 2019-11-26
• Subjects: Pyrimidine -- Antiplasmodial -- In Silico Docking -- Drug Resistance -- ADME Profile; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.201903031
• Languages: English
• ISSNs: 2365-6549

Abstract

Abstract: We report synthesis of new pyrimidine based molecular hybrids comprising of pyrimidine and aryl/heteroaryl groups linked, conveniently through 1, 2, 3‐triazole. In vitro antiplasdmodial activity of this series of compounds against chloroquine sensitive NF54 strain of the human malaria parasite Plasmodium falciparum, revealed interesting trends and correlation with the physicochemical properties of the hybrids. In silico docking of the most active (IC50 4.40±1.00 μM) (more active than reference artesunate) member 16 a in the active binding sites of wild type Pf DHFR‐TS ( P. falciparum Dihydrofolate Reductase‐Thymidylate Synthase) and Pf DHFR‐TS Quadruple mutant showed interactions suggesting their role as Pf DHFR inhibitors. Further, all the members of the series showed favorable in silico ADME (Adsorption Distribution, Metabolism, Excretion) profile. Abstract : Efficacious synthesis of a new series of pyrimidine‐based molecular hybrids is presented. The most active member of the series showed significant (IC50 4.40±1.00 μM) antiplasmodial activity against chloroquine sensitive NF54 strain of P. falciparum . M). In silico docking of the most active member in the active site of wild type Pf DHFR‐TS and Pf DHFR‐TS Quadruple mutant suggested their inhibitory role.