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Piperazine amides with desirable solubility, physicochemical and drug-like properties: Synthesis and evaluation of the anti-Trypanosoma cruzi activity

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Author(s):
Varela, Marina T. ; Romanelli, Maiara ; Amaral, Maiara ; Tempone, Andre G. ; Fernandes, Joao Paulo S.
Total Authors: 5
Document type: Journal article
Source: SAUDI PHARMACEUTICAL JOURNAL; v. 31, n. 7, p. 9-pg., 2023-06-01.
Abstract

The absence of effective chronic treatment, expansion to non-endemic countries and the significant bur -den in public health have stimulated the search for novel therapeutic options to treat Chagas disease, a protozoan disease caused by Trypanosoma cruzi. Despite current efforts, no new drug candidates were approved in clinical trials in the past five decades. Considering this, our group has focused on the expan-sion of a series (LINS03) with low micromolar activity against amastigotes, considering the optimization of pharmacokinetic properties through increasing drug-likeness and solubility. In this work, we report a new set of 13 compounds with modifications in both the arylpiperazine and the aromatic region linked by an amide group. Five analogues showed activity against intracellular amastigotes (IC50 17.8 to 35.9 lM) and no relevant cytotoxicity to mammalian cells (CC50 > 200 lM). Principal component analysis (PCA) was performed to identify structural features associated to improved activity. The data revealed that polarity, hydrogen bonding ability and flexibility were key properties that influenced the antipara-sitic activity. In silico drug-likeness assessments indicated that compounds with the 4-methoxycinammyl (especially compound 2b) had the most prominent balance between properties and activity in the series, as confirmed by SAR analysis.& COPY; 2023 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). (AU)

FAPESP's process: 21/04464-8 - Microbial and plant prototypes as drug candidates for protozoan neglected diseases and multidrug-resistant bacteria
Grantee:André Gustavo Tempone Cardoso
Support Opportunities: Regular Research Grants
FAPESP's process: 19/24028-8 - Substituted aryl-alkylamide-piperazines as multitarget ligands: synthesis and assessment of the activity on relevant targets for the treatment of CNS disorders
Grantee:João Paulo dos Santos Fernandes
Support Opportunities: Regular Research Grants
FAPESP's process: 19/14167-0 - Assessment of pharmacokinetic properties in early drug discovery: evaluation of promising antitrypanosoma compounds and hit-to-lead optimization
Grantee:Marina Themoteo Varela
Support Opportunities: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 18/03918-2 - Evaluation of the antiparasitic activity and cytotoxicity of natural products derivatives in Trypanosoma cruzi: design and synthesis of analogues potentially superior
Grantee:Marina Themoteo Varela
Support Opportunities: Scholarships in Brazil - Doctorate