Improved synthesis of 1,3,4-thiadiazolium-2-phenylamines using microwave and ultrasound irradiation and investigation of their cytotoxic activity

Abstract

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 ...

Mesoionic compounds with antifungal activity against Fusarium verticillioides

“…The mesoionic compounds were characterized using 1 H and 13 C NMR and IR spectroscopies. The 1 H and 13 C chemical shifts were assigned based on literature data [ 9 , 8 ], and were consistent with the structures proposed. The chemical shifts assigned to hydrogens linked to exocyclic nitrogen were observed in the range of 12.30-1.62 ppm, and the vinylic hydrogens in the range of 7.83-8.25 and 7.04-7.25 to H-α and H-β, respectively.…”

“…In this work, the antifungal activity of sixteen (16) compounds of the mesoionic class, namely 4-phenyl-5-(4’-X-styryl)-1,3,4-thiadiazolium-2-phenylamine chloride (series I, M-1 to M-9 ) and 4,5-diphenyl-1,3,4-thiadiazolium-2-(4’-Y-phenylamine) chloride (series II, M-10 to M-16 ), were evaluated against different mycotoxigenic fungi. The mesoionic derivatives were synthesized in accordance with the literature using a green chemistry method that utilized microwave irradiation and solvent-free conditions and resulted in good yields within a range of 90-98% [ 9 ]. The evaluated compounds could be grouped based on structural characteristics into two groups.…”

“…The mesoionic compounds ( MI ) were synthesized as previously reported [ 9 ]. Briefly, the substituted benzaldehydes (0.35 mmol) and thiosemicarbazides (0.35 mmol) were mixed in the presence of thionyl chloride and a few drops of 1,4-dioxane.…”

“…Mesoionic compounds are a special class of heterocyclic compounds having various biological activities such as antifungal, antitumor activities among other [ 6 - 9 ]. Possessing a betaine-like character with positive charge in a polyheteroatomic system and negatively charged atom or exocyclic group, these compounds are able to interact with biomolecules.…”

Microwave-Assisted Synthesis of New N1,N4-Substituted Thiosemicarbazones

“…Our research group has been working on more efficient and cleaner synthetic methods, focusing on microwave irradiation and solvent-free conditions [ 14 , 15 , 16 , 17 ]. To extend our investigation and considering the special importance of thiosemicarbazone class, in this paper we report the synthesis of thirty six thiosemicarbazones N 1 , N 4 -substituted from thiosemicarbazides with low reaction times and good yields by microwave-assisted reactions.…”