RESUMEN
New sets of functionalized thiazolidinone and thiadiazole derivatives were synthesized, and their cytotoxicity was evaluated on HepG2, MCF-7, HTC-116, and WI38 cells. The synthetic approach is based on the preparation of 4-(4-acetamidophenyl)thiosemicarbazide (4) and their thiosemicarbazones 5 a-e, which are converted to the corresponding thiazoldin-4-one compounds 6 a-e upon cyclization with ethyl bromoacetate. The thiadiazole compounds 9 and 12 were obtained by reacting 4-(4-acetamidophenyl)thiosemicarbazide with isothiocyanates and/or ethyl 2-cyano-3,3-bis(methylthio)acrylate, respectively. The thiazolidinone compounds 6 c and 6 e exhibited strong cytotoxicity against breast cancer cells, with an IC50 (6.70±0.5â µM) and IC50 (7.51±0.8â µM), respectively, very close to that of doxorubicin (IC50: 4.17±0.2â µM). In addition, the anti-cancer properties of the tested thiazolidinone and thiadiazole scaffolds were further explored by the molecular docking program (MOE)-(PDB Code-1DLS). Compounds 5 d, 5 e, 6 d, 6 e, and 7 have the best binding affinity, ranging from -8.5386â kcal.mol-1 to -8.2830â kcal.mol-1.
Asunto(s)
Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Tiadiazoles , Tiazolidinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Tiazolidinas/química , Tiazolidinas/farmacología , Tiazolidinas/síntesis química , Relación Estructura-Actividad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a DrogaRESUMEN
New thiazole and thiadiazole derivatives bound to the acetanilide moiety were synthesized and evaluated for their cytotoxic activity. The precursor N-(4-acetamidophenyl)-N'-phenylthiourea (2) was cyclocondensed with ethyl bromoacetate to afford a mixture of the two isomers, 2-(4-acetamidophenylimino)-3-phenylthiazolidin-4-one (3a, 23%) and 3-(4-acetamidophenyl)-2-phenyliminothiazolidin-4-one (3b, 71%). The Knoevenagel reaction of 3b with various aromatic aldehydes afforded 5-arylidene-2-phenyliminothiazolidin-4-one derivatives 5a-5e. Intramolecular cyclization of thiourea scaffold 2 with chloroacetone and/or phenacyl chloride gave the conforming thiazole derivatives 6a and 6b. A new series of thiadiazole derivatives 9a-9c and 11a-11c was synthesized by the reaction of N-(4-acetamidophenyl)-N'-phenylthiourea (2) with selected derivatives of hydrazonoyl halide in ethanol and triethylamine. The structures of the synthesized thiazole and thiadiazole compounds were elucidated by their compatible spectral data. The cytotoxic activity of the synthesized thiazole and thiadiazole derivatives was screened against four human cancer cell lines and showed promising results. Thiazolidin-4-one compound 5d showed the strongest cytotoxic effects on hepatocellular carcinoma (IC50 = 8.80 ± 0.31 µg/mL), mammary gland breast cancer (IC50 = 7.22 ± 0.65 µg/mL) and colorectal carcinoma (IC50 = 9.35 ± 0.61 µg/mL) cell lines.