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Design of new cruzain inhibitors as drug candidates for the treatment of Chagas\' disease

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Ivaní Pauli
Total Authors: 1
Document type: Doctoral Thesis
Press: São Carlos.
Institution: Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT)
Defense date:
Examining board members:
Adriano Defini Andricopulo; Fábio Cardoso Cruz; Javier Alcides Ellena; Marco Edilson Freire de Lima; Norberto Peporine Lopes
Advisor: Adriano Defini Andricopulo

Chagas\' disease is considered a high priority neglected tropical disease by the World Health Organization in its research and development programs. It is a serious public health problem, being among the main causes of cardiac disorders in many countries in Latin America. The absence of an effectite treatment makes urgent the pursue of novel therapeutic options. In this way, the goal of this PhD thesis was to develop inhibitors of the enzyme cruzain, the main cysteine protease from Trypanosoma cruzi, a validated target for Chagas\' disease drug discovery. This work involved the combination of experimental and computational approaches in medicinal chemistry and drug design. Two sets of inhibitors were used as lead compounds: benzimidazole and imide derivatives. The design, chemical synthesis and biological evaluation of several compounds were performed iteratively, until the optimization of potency was achieved. Modifications in different regions of each lead compound were explored, making it possible to understand the SAR requirements for enzyme inhibition. The mode of inhibition of the compounds was determined. Preliminary toxicity studies were caried out using cellular lineages and mice, showing that the compounds possess a safe profile. A PhD internship at the department of metabolism and pharmacokinetics at the U.S. pharmaceutical company AbbVie led to the determination and optimization of the pharmacokinetic profile of the inhibitors. Besides, a methodology recently implemented in the company was employed in this work, which aims a multi parametric optimization of the test compounds. This method was used to identify drug candidates with a favorable balance between potency and pharmacokinetic parameters, which are absolutely essential to develop a new, safe and effective drug. Finally, it was created a rational and more effective strategy for the screening of new antichagasic drug candidates, presenting an optimized combinaiton of potency and ADME properties. (AU)

FAPESP's process: 11/13789-6 - Design of Inhibitors of the Enzyme Cruzain as Drug Candidates for the Treatment of Chagas Disease
Grantee:Ivaní Pauli
Support Opportunities: Scholarships in Brazil - Doctorate