title: Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors.
abstract: A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A Ki value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 μM was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds.
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Leandro A A
authors.initials: LA
authors.lastname: Avelar
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Cristian D
authors.initials: CD
authors.lastname: Camilo
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Sérgio
authors.initials: S
authors.lastname: de Albuquerque
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil; University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, California, United States of America.
authors.forename: William B
authors.initials: WB
authors.lastname: Fernandes
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Gonçalez
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kenny
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Andrei
authors.initials: A
authors.lastname: Leitão
authors.affiliation: University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, California, United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Montanari
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Erika V Meñaca
authors.initials: EV
authors.lastname: Orozco
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Jean F R
authors.initials: JF
authors.lastname: Ribeiro
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Josmar R
authors.initials: JR
authors.lastname: Rocha
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rosini
authors.affiliation: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Saidel
mesh_terms: D001665:Binding Sites; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D009570:Nitriles; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi