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A new chemotype with promise against Trypanosoma cruzi.

ABSTRACT: Pyridyl benzamide 2 is a potent inhibitor of Trypanosoma cruzi, but not other protozoan parasites, and had a selectivity-index of ?10. The initial structure-activity relationship (SAR) indicates that benzamide and sulfonamide functional groups, and N-methylpiperazine and sterically unhindered 3-pyridyl substructures are required for high activity against T. cruzi. Compound 2 and its active analogs had low to moderate metabolic stabilities in human and mouse liver microsomes.

SUBMITTER: Wang X

PROVIDER: S-EPMC6892603 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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A new chemotype with promise against Trypanosoma cruzi.

Wang Xiaofang X Cal Monica M Kaiser Marcel M Buckner Frederick S FS Lepesheva Galina I GI Sanford Austin G AG Wallick Alexander I AI Davis Paul H PH Vennerstrom Jonathan L JL

Bioorganic & medicinal chemistry letters 20191031 1

Pyridyl benzamide 2 is a potent inhibitor of Trypanosoma cruzi, but not other protozoan parasites, and had a selectivity-index of ≥10. The initial structure-activity relationship (SAR) indicates that benzamide and sulfonamide functional groups, and N-methylpiperazine and sterically unhindered 3-pyridyl substructures are required for high activity against T. cruzi. Compound 2 and its active analogs had low to moderate metabolic stabilities in human and mouse liver microsomes. ...[more]

PMID: 31706668

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Project description:Chagas disease is a major health problem in Latin America, and an emerging infectious disease in the US. Previously, we have screened the Trypanosoma cruzi sequence database by a computational/bioinformatics approach, and identified antigens that exhibited the characteristics of vaccine candidates.We investigated the protective efficacy of a multi-component DNA-prime/protein-boost vaccine (TcVac2) constituted of the selected candidates and cytokine (IL-12 and GM-CSF) expression plasmids in a murine model. C57BL/6 mice were immunized with antigen-encoding plasmids plus cytokine adjuvants, followed by recombinant proteins; and two-weeks later, challenged with T. cruzi trypomastigotes. ELISA and flow cytometry were employed to measure humoral (antibody isotypes) and cellular (lymphocyte proliferation, CD4(+) and CD8(+) T cell phenotype and cytokines) responses. Myocardial pathology was evaluated by H&E and Masson's trichrome staining.TcVac2 induced a strong antigen-specific antibody response (IgG2b>IgG1) and a moderate level of lymphocyte proliferation in mice. Upon challenge infection, TcVac2-vaccinated mice expanded the IgG2b/IgG1 antibodies and elicited a substantial CD8(+) T cell response associated with type 1 cytokines (IFN-gamma and TNF-alpha) that resulted in control of acute parasite burden. During chronic phase, antibody response persisted, splenic activation of CD8(+) T cells and IFN-gamma/TNF-alpha cytokines subsided, and IL-4/IL-10 cytokines became dominant in vaccinated mice. The tissue parasitism, inflammation, and fibrosis in heart and skeletal muscle of TcVac2-vaccinated chronic mice were undetectable by histological techniques. In comparison, mice injected with vector or cytokines only responded to T. cruzi by elicitation of a mixed (type 1/type 2) antibody, T cell and cytokine response, and exhibited persistent parasite burden and immunopathology in the myocardium.TcVac2-induced activation of type 1 antibody and lymphocyte responses provided resistance to acute T. cruzi infection, and consequently, prevented the evolution of chronic immunopathology associated with parasite persistence in chagasic hearts.

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A new chemotype with promise against Trypanosoma cruzi.

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A new chemotype with promise against Trypanosoma cruzi.

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