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.

We present an efficient procedure for the synthesis of thirty-six N1,N4-substituted thiosemicarbazones, including twenty-five ones that are reported for the first time, using a microwave-assisted methodology for the reaction of thiosemicarbazide intermediates with aldehydes in the presence of glacial acetic acid in ethanol and under solvent free conditions. Overall reaction times (20–40 min when ethanol as solvent, and 3 min under solvent free conditions) were much shorter than with the traditional procedure (480 min); satisfactory yields and high-purity compounds were obtained. The thiosemicarbazide intermediates were obtained from alkyl or aryl isothiocyanates and hydrazine hydrate or phenyl hydrazine by stirring at room temperature for 60 min or by microwave irradiation for 30 min, with lower yields for the latter. The preliminary in vitro antifungal activity of thiosemicarbazones was evaluated against Aspergillus parasiticus and Candida albicans.

Uma nova e eficiente síntese de oito derivados da classe 1,3,4-tiadiazolio-2-fenilaminas (1-8, sendo o derivado 8 inédito na literatura) foi realizada utilizando cloreto de tionila ou cloreto de trimetilsilano como catalisadores sob irradiação de microondas ou ultra-som. Os compostos alvos foram obtidos em bons rendimentos e em tempo extraordinariamente curtos, 5 min sob irradiação de microondas e 10 min sob irradiação de ultra-som, quando comparados com a metodologia tradicional (24 a 48 h em repouso a temperatura ambiente). Os melhores rendimentos foram obtidos usando irradiação de microondas e, de maneira geral, usando o cloreto de tionila ao invés de cloreto de trimetilsilano. A citotoxicidade foi avaliada frente à linhagem de leucemia humana K562 e do linfoma Daudi, apresentando resultados promissores para o derivado cloreto de 4-fenil-5-(4'-nitro-estiril)-1,3,4-tiadiazolio-2-fenilamina.A new and efficient synthesis of eight 1,3,4-thiadiazolium-2-phenylamine derivatives (1-8, where 8 is novel in the literature) was performed using thionyl chloride or trimethylsilyl chloride as catalysts under microwave or ultrasound irradiation. The target compounds were obtained in good yields and remarkably short times, 5 min under microwave irradiation and 10 min under ultrasound irradiation, where compared to traditional methodology (24 to 48 h at room temperature standing). The best yields were obtained using the microwave irradiation and, in general way, using thionyl chloride instead trimethylsilyl chloride. The cytotoxicity against K562 human leukemia and Daudi lymphoma lines was evaluated and showed promising results from the 4-phenyl-5-(4'-nitro-styryl)-1,3,4-thiadiazolium-2-phenylamine chloride derivative.Keywords: mesoionic heterocycle compounds, microwave, ultrasound, cytotoxic activity IntroductionMesoionic compounds are a special class of heterocycles with potential therapeutic applications due to their unique chemical properties. They possess a betaine-like character with a partial positive charge on the heterocyclic ring that is balanced by a negative charge located on an exocyclic atom or group.1,2 The large separation between the charged regions leads to large dipole moments of about 4-5 D.3,4 These properties suggest the possibility of interacting with biomolecules such as proteins and DNA. Additionally, the overall neutral character of these compounds enables them to cross biological membranes. Different classes of mesoionic compounds have demonstrated a wide range of biological activities such as anti-inflammatory and analgesic, 5 antiparasitic, 6,7 antibacterial, 8,9 antiplatelet, fibrinolytic, thrombolytic and broncholytic effects, 10 as well as anticancer potency.11-17 The promising therapeutic applications have led us to study these interesting compounds in our laboratory. We have previously described the survival enhancement of Ehrlich and Sarcoma 180 tumor-bearing mice treated with 4-phenyl-5-(4'-X-styryl)-1,3,5-thiadiazolium-2-phenylamine chlorides.12 Respiratory chain inhibition, transmembrane ...

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BackgroundFungi contaminate the food of humans and animals, are a risk to health, and can cause financial losses. In this work, the antifungal activities of 16 mesoionic compounds (MI 1–16) were evaluated against mycotoxigenic fungi, including Aspergillus spp., Fusarium verticillioides and Penicillium citrinum. Furthermore, the decreased ergosterol in the total lipid content of Fusarium verticillioides was investigated.ResultsF. verticillioides was the most sensitive fungus to the mesoionic compounds. Among the evaluated compounds, MI-11 and MI-16 presented higher antifungal effects against F. verticillioides, with MIC values of 7.8 μg/ml, and MI-2 and MI-3 followed, with MICs of 15.6 μg/ml. The most active compounds were those with heterocyclic ring phenyl groups substituted by electron donor moieties (MI-11 and MI-16). Among some compounds with higher activity (MI-2, MI-11 and MI-16), decreased ergosterol content in the total lipid fraction of F. verticillioides was demonstrated. MI-2 reduced the ergosterol content approximately 40% and 80% at concentrations of 7.8 μg/ml and 15.6 μg/ml, respectively, and MI-11 and MI-16 decreased the content by 30% and 50%, respectively, when at a concentration of 7.8 μg/ml.ConclusionThese findings indicate that mesoionic compounds have significant antifungal activity against F. verticillioides.