Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents.
In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones.
Department of Pharmaceutical Sciences, Centre for Health Science, Federal University of Pernambuco, 50740-520 Recife, PE, Brazil.
Marcelo Zaldini
MZ
Hernandes
Marcelo Montenegro
MM
Rabello
Ana Cristina Lima
AC
Leite
Marcos Veríssimo Oliveira
MV
Cardoso
Diogo Rodrigo Magalhaes
DR
Moreira
Dalci José
DJ
Brondani
Carlos Alberto
CA
Simone
Luiza Campos
LC
Reis
Marina Assis
MA
Souza
Valéria Rego Alves
VR
Pereira
Rafaela Salgado
RS
Ferreira
James Hobson
JH
McKerrow
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003198:Computer Simulation; D057056:Cysteine Proteases / Q000737:chemistry / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D005260:Female; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects
D015853:Cysteine Proteinase Inhibitors; D006835:Hydrazones; D014230:Triazoles; D014344:Trypanocidal Agents; D057056:Cysteine Proteases