Synthesis and SAR of new isoxazole-triazole bis-heterocyclic compounds as analogues of natural lignans with antiparasitic activity

Bioorganic & Medicinal Chemistry
Lara Almida ZimmermannLilian Sibelle Campos Bernardes

Abstract

Despite the impressive scientific and technological advances of recent decades, no effective treatment is currently available for Chagas disease. Our research group has been studying the design and synthesis of analogues of natural lignans aiming to identify compounds with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivatives and the structure-activity relationship study conducted based on results of biological assays against Trypanosoma cruzi amastigotes. Thirty-seven compounds were active, and eight of them had GI50 values lower than 100 μM (GI50 88.4-12.2 μM). A qualitative structure activity relationship study using three dimensional descriptors was carried out and showed a correlation between growth inhibitory potency and the presence of bulky hydrophobic groups located at rings A and D of the compounds. Compound 3-(3,4-dimethoxyphenyl)-5-((4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)methyl)isoxazole (31) was the most active in the series (GI50 12.2 μM), showing, in vitro, low toxicity and potency similar to benznidazole (GI50 10.2 μM). These results suggest that this compound can be a promising scaffold for the design of new trypanocidal compounds.

References

Mar 29, 2001·Journal of Pharmacological and Toxicological Methods·C A Lipinski
Oct 24, 2001·The Journal of Organic Chemistry·Hugo E. GottliebAbraham Nudelman
Aug 13, 2002·Current Topics in Medicinal Chemistry·Armin Schmidt, R Luise Krauth-Siegel
Apr 24, 2003·Parasitology Research·R Luise Krauth-Siegel, Oliver Inhoff
Jan 6, 2005·Journal of the American Chemical Society·Fahmi HimoValery V Fokin
Sep 10, 2005·The Journal of Organic Chemistry·Trond V HansenValery V Fokin
Aug 16, 2006·Bioorganic & Medicinal Chemistry·Lilian Sibelle Campos BernardesIvone Carvalho
Sep 25, 2007·Phytochemistry·Lidiane Gaspareto FelippeMaysa Furlan
Dec 7, 2013·European Journal of Medicinal Chemistry·Mohammad ArshadInho Choi
Dec 21, 2013·Bioorganic & Medicinal Chemistry·Nisha SinghVinod K Tiwari
Dec 1, 2004·Drug Discovery Today. Technologies·Christopher A Lipinski
Aug 12, 2014·Infectious Diseases of Poverty·Zulfiqar A BhuttaJai K Das
Feb 9, 2016·Journal of Natural Products·David J Newman, Gordon M Cragg
Feb 6, 2017·European Journal of Medicinal Chemistry·Rafael da RosaLílian Sibelle Campos Bernardes
Feb 28, 2017·Nature Reviews. Microbiology·Mark C FieldIan H Gilbert
Jun 13, 2017·European Journal of Medicinal Chemistry·Angelika Sysak, Bożena Obmińska-Mrukowicz
Jul 6, 2017·Drug Discovery Today·Elisa BonandiDaniele Passarella
Jun 2, 2018·Bioorganic & Medicinal Chemistry·Jie ZhuHao-Peng Sun
Jul 24, 2018·European Journal of Medicinal Chemistry·Cauê Benito ScarimMan Chin Chung

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Citations

Apr 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Theo BattistaAnnarita Fiorillo
Aug 1, 2021·ChemistryOpen·Fernanda Andreia RosaCelso Vataru Nakamura
Oct 1, 2021·Chemical Biology & Drug Design·Bhavna SarohaSuresh Kumar

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