Synthesis, X-ray crystallographic analysis, DFT studies and biological evaluation of triazolopyrimidines and 2-anilinopyrimidines

Publication Name

Journal of Molecular Structure

Abstract

Inspired by the reported antiviral activity of pyrimidines and triazolopyrimidines, two series of 2-anilinopyrimidines (5a-e) and 1-aryl-[1,2,4]triazolo[4,3-a]pyrimidines (14a-k) were designed and synthesized as potential antiviral agents. X-ray crystallographic study of compounds (14d) and (14k) confirmed the structure of the desired isomer and revealed the coplanarity of the fused [1,2,4]triazolo[4,3-a]pyrimidine rings with the aryl side group. DFT studies revealed insights into the mechanism of the micro-reversible cyclisation step using DFT [B3LYP-D3(BJ)/6–31++G(d,p)]. The pharmacokinetic properties and calculation of drug likeness scores (DLS) of (5a-e) and (14a-k) suggested good traditional drug-like properties and led to the synthesis of derivatives (14a-k) which were evaluated for their anti-viral activity with the most potent derivatives subjected to cytotoxicity screening. Compounds (14a), (14c), (14e), (14f) and (14k) showed moderate to strong antiviral activity with EC50 values 38 - 186 μM. Compound (14e) (DLS = 0.29) showed the best anti-CHIKV activity (EC50 = 38 μM) and lowest cytotoxicity (CC50 > 300 μg/ml) against breast cancer cell lines, MCF-7 and MD-AMB-231 and normal cell line EA.hy926. Simplification of [1,2,4]triazolo[4,3-a]pyrimidine ring, led to series (5a-e) (DLS = 0.03 - 0.77). Derivatives (5a-d) showed fair anti-CHIKV activity (EC50 > 200 μM), while (5e) emerged as the most active antiviral agent, however the most cytotoxic.

Open Access Status

This publication is not available as open access

Volume

1252

Article Number

132092

Funding Sponsor

University of Sydney

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Link to publisher version (DOI)

http://dx.doi.org/10.1016/j.molstruc.2021.132092