Chemical synthesis and biological activity of semisynthetic derivatives against Chagas disease and leishmaniasis composed of fragments of natural products and 1,2,3-triazine 1-oxide scaffold

Chagas disease and leishmaniasis are neglected diseases caused by Trypanosoma cruzi and Leishmania sp ., respectively, leading to morbidity and mortality worldwide and affecting more than 6 million people per year. Despite the availability of treatments, their low efficacy and several adverse effects encourage the design and development of new drugs. The hybridization of natural products with heterocyclic scaffolds has been a molecular editing strategy for obtaining new drugs with antiparasitic activity. In this project, a new series of semisynthetic 4-carboxylate-1,2,3-triazine 1-oxide derivatives was designed, synthesized, and evaluated in vitro and in vivo against two strains of T. cruzi and L. mexicana . Compound TS-14 with the geranyl ester group at the 4-position and the ethyl group at the 5-position on the 1,2,3-triazine 1-oxide ring had better trypanocidal activity against Ninoa (IC 50 = 1.75 µM) and A1 (IC 50 =1.16 µM) strains than the reference drugs benznidazole (IC 50 = 30.3 µM and 39.8 µM, respectively) and nifurtimox (IC 50 = 7.09 µM and 19.3 µM, respectively). Additionally, TS-14 reduced parasitemia by 40.4% against T. cruzi trypomastigotes in an in vivo model. Compound TS-16 , featuring a geranyl ester group at the 4-position and an n-pentyl group at the 5-position on the 1,2,3-triazine 1-oxide ring, exhibited better leishmanicidal activity against FCQEPS (IC 50 = 12.97 µM) and M379 (IC 50 = 2.11 µM) strains than the reference drug glucantime (IC 50 = 125.23 µM and 133.96 µM, respectively). Additionally, TS-21 and TS-30 cause the highest parasitemia reduction (60% and 64.1%, respectively) against L. mexicana in an in vivo assay. Finally, compounds TS-14 and TS-32 showed an inhibitory effect uncompetitive on trypanothione reductase of T. cruzi ( Tc TryR) and the compound TS-32 on trypanothione synthetase of T. cruzi ( TcTryS ). This study represents an innovative case of the use of fragments of natural products hybridized with 1,2,3-triazine 1-oxide scaffold as a new option for the development of drugs against parasites such as T. cruzi and L. mexicana .