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

Fares, M; Canfield, P; Alsherbiny, MA; Lewis, W; Willis, AC; Guang Li, C; Neyts, J; Jochmans, D; Gale, PA; Keller, PA

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

Fares, M Canfield, P Alsherbiny, MA Lewis, W Willis, AC Guang Li, C Neyts, J Jochmans, D Gale, PA Keller, PA

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Journal of Molecular Structure, 2022, 1252, pp. 132092
Issue Date:: 2022-03-15

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Field	Value	Language
dc.contributor.author	Fares, M
dc.contributor.author	Canfield, P
dc.contributor.author	Alsherbiny, MA
dc.contributor.author	Lewis, W
dc.contributor.author	Willis, AC
dc.contributor.author	Guang Li, C
dc.contributor.author	Neyts, J
dc.contributor.author	Jochmans, D
dc.contributor.author	Gale, PA
dc.contributor.author	Keller, PA
dc.date.accessioned	2023-02-08T00:39:18Z
dc.date.available	2023-02-08T00:39:18Z
dc.date.issued	2022-03-15
dc.identifier.citation	Journal of Molecular Structure, 2022, 1252, pp. 132092
dc.identifier.issn	0022-2860
dc.identifier.uri	http://hdl.handle.net/10453/165985
dc.description.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.
dc.language	en
dc.publisher	Elsevier
dc.relation.ispartof	Journal of Molecular Structure
dc.relation.isbasedon	10.1016/j.molstruc.2021.132092
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0306 Physical Chemistry (incl. Structural), 0307 Theoretical and Computational Chemistry
dc.subject.classification	Inorganic & Nuclear Chemistry
dc.title	Synthesis, X-ray crystallographic analysis, DFT studies and biological evaluation of triazolopyrimidines and 2-anilinopyrimidines
dc.type	Journal Article
utslib.citation.volume	1252
utslib.for	0306 Physical Chemistry (incl. Structural)
utslib.for	0307 Theoretical and Computational Chemistry
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
utslib.copyright.status	closed_access	*
dc.date.updated	2023-02-08T00:39:17Z
pubs.publication-status	Published
pubs.volume	1252

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.

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