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Molecular design, trypanocidal and anticancer activities of covalent reversible inhibitors of cysteine proteases

Grant number: 14/07292-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2014
Effective date (End): December 03, 2018
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Carlos Alberto Montanari
Grantee:José Carlos Quilles Junior
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated research grant:13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, AP.TEM


All the synthesised NEQUIMED compounds, supported by FAPESP Processes 2011/01893-3, 2011/20572-3 e 2008/04127-7, were active against cruzain in the range of low- to sub-micromolar concentrations. The most potent compound, Nequimed409 (Neq409), inhibited the enzyme with IC50 of 1.89 ± 0.11 µM (pIC50 = 5.7). These compounds showed trypanocidal activity against the trypomastigote/amastigote infective form Tulahuen lacZ strain at concentrations less than 50 µM. The prototype compound Neq409, potent against cruzain is also a trypanocidal agent (concentration-dependent response) with IC50 of 2.7 ± 0.3 µM (pIC50 = 5.6). Neq409 is more potent than the drug benznidazole (BZ), which was used as control (pIC50 = 4.6) and has minimal cytotoxicity in mice spleen (> 500 µM, comparable to BZ which is > 500 µM). The most promising dipeptidyl nitriles exhibit characteristics of leads that can be optimized for drug candidates: T. cruzi pIC50 > 5 (pIC50 (Neq409) = 5.6) with SI > 10 (SI ratio = IC50(cyto)/IC50(T. cruzi) = 185, BZ = 20.6); PFI < 8 (PFINeq409 = 3.7); # Ar rings < 5 and MW 500 < Da. Substances of this class are also inhibitors of cathepsin L (CatL, other cysteine protease). Inhibiting the activity of specific proteases like CatL may slow the progression of cancer. In preliminary studies at NEQUIMED/IQSC/USP we demonstrated that Neq0409, a cruzain inhibitor, is also a CatL inhibitor. Therefore, this proposal aims to conduct an extrathermodynamic study of structure-activity relationships (TD-SAR) in order to validate the hypothesis that cruzain inhibitors are CatL inhibitors and that the same series of inhibitors also have activity against lines of prostate and pancreatic cancer. (AU)

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
QUILLES, JR., JOSE C.; SHAMIM, ANWAR; TEZUKA, DAIANE Y.; BATISTA, PEDRO H. J.; LOPES, CARLA D.; DE ALBUQUERQUE, SERGIO; MONTANARI, CARLOS A.; LEITAO, ANDREI. Dipeptidyl nitrile derivatives suppress the Trypanosoma cruzi in vitro infection. Experimental Parasitology, v. 219, . (18/03985-1, 14/07292-0, 18/15904-6, 13/18009-4)
QUILLES JUNIOR, JOSE C.; ROCHO CARLOS, FERNANDA DOS REIS; MONTANARI, A.; LEITAO, ANDREI; MIGNONE, VIVIANE W.; ARRUDA, MARIA AUGUSTA; TURYANSKA, LYUDMILA; BRADSHAW, TRACEY D.. Apoferritin encapsulation of cysteine protease inhibitors for cathepsin L inhibition in cancer cells. RSC ADVANCES, v. 9, n. 63, p. 36699-36706, . (13/18009-4, 14/07292-0)
QUILLES JR, JOSE C.; TEZUKA, DAIANE Y.; LOPES, CARLA D.; RIBEIRO, FERNANDA L.; LAUGHTON, CHARLES A.; DE ALBUQUERQUE, SERGIO; MONTANARI, CARLOS A.; LEITAO, ANDREI. Dipeptidyl nitrile derivatives have cytostatic effects against Leishmania spp. promastigotes. Experimental Parasitology, v. 200, p. 84-91, . (14/07292-0, 13/18009-4)
QUILLES JR, JOSE C.; BERNARDI, MURILLO D. L.; BATISTA, PEDRO H. J.; SILVA, SAMELYN C. M.; ROCHA, CAMILA M. R.; MONTANARI, CARLOS A.; LEITAO, ANDREI. Biological Activity and Physicochemical Properties of Dipeptidyl Nitrile Derivatives Against Pancreatic Ductal Adenocarcinoma Cells. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v. 19, n. 1, p. 112-120, . (14/07292-0, 13/18009-4)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
QUILLES JUNIOR, José Carlos. Molecular design, trypanosomicidal and anticancer activity of reversible covalent inhibitors of cysteine proteases. 2019. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Química de São Carlos (IQSC/BT) São Carlos.

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