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.
Hernandes
Marcelo Zaldini
MZ
Department of Pharmaceutical Sciences, Centre for Health Science, Federal University of Pernambuco, 50740-520 Recife, PE, Brazil.
Rabello
Marcelo Montenegro
MM
Leite
Ana Cristina Lima
AC
Cardoso
Marcos Veríssimo Oliveira
MV
Moreira
Diogo Rodrigo Magalhaes
DR
Brondani
Dalci José
DJ
Simone
Carlos Alberto
CA
Reis
Luiza Campos
LC
Souza
Marina Assis
MA
Pereira
Valéria Rego Alves
VR
Ferreira
Rafaela Salgado
RS
McKerrow
James Hobson
JH
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