Investigation of trypanothione reductase inhibitory activity by 1,3,4-thiadiazolium-2-aminide derivatives and molecular docking studies.
The biological activities of a series of mesoionic 1,3,4-thiadiazolium-2-aminide derivatives have been studied. The most active compounds (MI-HH; MI-3-OCH(3); MI-4-OCH(3) and MI-4-NO(2)) were evaluated to determine their effect on trypanothione reductase (TryR) activity in Leishmania sp. and Trypanosoma cruzi. Among the assayed compounds, only MI-4-NO(2) showed enzyme inhibition effect on extracts from different cultures of parasites, which was confirmed using the recombinant enzyme from T. cruzi (TcTryR) and Leishmania infantum (LiTryR). The enzyme kinetics determined with LiTryR demonstrated a non-competitive inhibition profile of MI-4-NO(2). A molecular docking study showed that the mesoionic compounds could effectively dock into the substrate binding site together with the substrate molecule. The mesoionic compounds were also effective ligands of the NADPH and FAD binding sites and the NADPH binding site was predicted as the best of all three binding sites. Based on the theoretical results, an explanation at the molecular level is proposed for the MI-4-NO(2) enzyme inhibition effect. Given TryR as a molecular target, it is important to continue the study of mesoionic compounds as part of a drug discovery campaign against Leishmaniasis or Chagas' disease.
Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica de Tripanosomatídeos, Avenida Brasil 4365, Manguinhos, Rio de Janeiro, RJ, Brazil. rakelbio@gmail.com
Raquel F
RF
Rodrigues
Denise
D
Castro-Pinto
Aurea
A
Echevarria
Camilla M
CM
dos Reis
Catarina N
CN
Del Cistia
Carlos Mauricio R
CM
Sant'Anna
Filipa
F
Teixeira
Helena
H
Castro
Marilene
M
Canto-Cavalheiro
Leonor L
LL
Leon
Ana
A
Tomás
D000818:Animals; D006801:Humans; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
C539945:1,3,4-thiadiazolium-2-aminide; D013830:Thiadiazoles; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase