Synthesis and Antiprotozoan Properties of New 3,5-Disubstituted-tetrahydro-2H-1,3,5-thiadiazine-2-thione Derivatives

Abstract

In a search for antiprotozoan compounds, 34 new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives were synthesized and tested in vitro against Trypanosoma cruzi and Trichomonas vaginalis. Some of them showed important antiprotozoan activity. In vivo assays of compounds which showed remarkable in vitro activity against T. vaginalis were carried out.

In Vitro and In Vivo High-Throughput Assays for the Testing of Anti-Trypanosoma cruzi Compounds

“…Extracellular epimastigotes are easily obtained and thus are often used as a first step in the screening of new potential anti- T. cruzi drugs in vitro [39]. To address whether fluorescent tdTomato parasites were useful to screen for such compounds, we plated tdTomato epimastigotes with or without the proven anti- T. cruzi compound benznidazole (BZ) and the fluorescence intensity as a representative of parasite growth was measured daily.…”

Thiadiazine Derivatives as Antiprotozoal New Drugs

“…The most used procedure to obtain the THTT derivatives is the reaction of the appropriate amine 1 with carbon disulfide 2 and potassium hydroxide 3 , to give the dithiocarbamate potassium salt 4 (which was not isolated), followed by cyclocondensation with formaldehyde 5 and the selected amino acids [9-11, 13-15], pseudo peptides [9-11, 13-18], and amines or amino ester ( 6 ) [12] able to provide the nitrogen at 5th position of the thiadiazine ring in fair to moderate or good yields. In the first step of these synthetic procedures, water is employed as a protic polar solvent in order to stabilize the dithiocarbamate intermediate 4 , in the second step pH 7-8 phosphate buffer was used (Scheme 1 ) [9-18].…”

“…In the first step of these synthetic procedures, water is employed as a protic polar solvent in order to stabilize the dithiocarbamate intermediate 4 , in the second step pH 7-8 phosphate buffer was used (Scheme 1 ) [9-18]. …”

“…The principal studies on the THTT derivatives [9-26] take into account the molecular structure of these molecules to obtain the best activity/cytotoxicity relation. In this context, we found in the bibliography the reports on many compounds with one THTT ring as the central core with a great variety of substituents in N-3 and N-5 position (mono-THTT) [9-18].…”

“…In this context, we found in the bibliography the reports on many compounds with one THTT ring as the central core with a great variety of substituents in N-3 and N-5 position (mono-THTT) [9-18]. In the last years, to enhance the antiprotozoal effect two THTT rings were incorporated into the same molecular structure, connected to each other via their N-3 atom by a linear or branch aliphatic backbone and bearing alkyl or carboxyalkyl residues at N-5 (bis-THTT)[19-26] (Fig.…”