Investigation of trypanothione reductase inhibitory activity by 1,3,4-thiadiazolium-2-aminide derivatives and molecular docking studies

Abstract

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.

Synthesis and Antifungal Activity AgainstCandidaStrains of Mesoionic System Derived From 1,3-Thyazolium-5-thiolate

“…In 7c, due to R 1 = CH 2 CH 3 , the CH 3 and the CH, from the isopropyl group, appear as a double doublet and a multiplet, respectively. In 7d, one more signal appears as a singlet around d 2.25 ppm due to the methyl group from the R 2 = CH 3 . In 7g, the integrals for the isopropyl group (H-15, H-16 and H-16') are for twelve hydrogens for CH 3 and two hydrogen for CH due to R 1 = CH(CH 3 ) 2 .…”

“…In 7d, one more signal appears as a singlet around d 2.25 ppm due to the methyl group from the R 2 = CH 3 . In 7g, the integrals for the isopropyl group (H-15, H-16 and H-16') are for twelve hydrogens for CH 3 and two hydrogen for CH due to R 1 = CH(CH 3 ) 2 . In 7h, one more signal appears around d 3.75 ppm with integral for three hydrogens from the methoxy group in R 1 .…”

“…[1][2][3][4][5][6][7] Such applications could be attributed to their peculiar chemical characteristics such as their betainic and planar characters, which allow strong interactions with biomolecules, their relatively small size, and the separation of the electron density (positive in the ring and negative in the exocyclic side chain), giving them amphiphilic properties. 8 Among all those applications, the antimicrobial activity has been highlighted in the last decades especially due to the development of resistant fungus strains associated with drugs that are no longer effective.…”

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

“…Since the early 1990s, a large number of trypanothione reductase inhibitors that do not affect human glutathione reductase has been identified (for review, see [172]). The search for new scaffold trypanothione reductase inhibitors is progressing by means of traditional whole cell screenings and in silico structure-based virtual screenings [162,173], but so far there are no new molecules in this category are under development.…”

Synthesis and preliminary ex vivo evaluation of the spasmolytic activity of 1,3-thiazolium- and 1,3,4-thiadiazolium-5-methylthio- and 5-thioacetate derivatives

“…In the latter area, the literature describes a wide range of biological activities associated with this class of compounds, including, among others, analgesic, anti-inflammatory, anticancer, antimicrobial, antihypertensive, antiplatelet, thrombolytic, trypanocidal and leishmanicidal activities (7)(8)(9)(10)(11)(12)(13).…”