Síntese, atividade antitumoral e antimicrobiana de novos derivados 3-[2-tioxo-3- (alquilaminometil)-1,3,4-oxadiazol-5-IL] -β- carbolínicos-1-fenilssubstituídos

Abstract

The β-carbolines alkaloids are a class of synthetic and naturally occurring compounds that possess a large spectrum of important pharmacological properties such as, antimicrobial, antitumoral and antiviral. Studies on a variety of synthetic β-carboline derivatives have demonstrated the influence of the substituents in positions-1 and -3 of the β-carboline skeleton on activity. The potentialities of β-carboline alkaloids as antitumoral agents and the importance of the search for new anticancer drugs have lead us to study this class of compounds. Our previous work on the synthesis and activity evaluation of 1-substituted-phenyl β-carbolines bearing the 2-thioxo-1,3,4-oxadiazol-5-yl nucleus showed the potential of these compounds as anticancer and antimicrobial agents. Furthermore, several Mannich bases derivate from 1,3,4- oxadiazole were reported to possess antitumoral activities. Taking in account our previous results and the activity reported for Mannich bases of 1,3,4-oxadiazole, in the present investigation we have designed and synthesized a number of new β-carboline derivatives bearing a 2- thioxo-3-alkylaminomethyl-1,3,4-oxadiazol-5-yl at C-3 of the β-carboline nucleus. In the synthetic route for the preparation of β-carboline-3-carbohydrazides (22 a-c) the intermediates methyl β-carboline-3-carboxylates (21 a-c) were prepared through a Pictet-Spengler condensation of L-tryptophan methyl ester with appropriate aromatic aldehydes in acid media, and subsequent oxidation with sulfur, in xylene. The reaction of 21 a-c with hydrazine hydrate in ethanol furnished the 1-(substituted-phenyl)-β-carboline-3- carbohydrazides (22 a-c). For preparation of 3-(2-thioxo-1,3,4-oxadiazol-5-yl) β-carbolines (23 a-c), the key intermediates 22 a-c were subjected to reaction with carbon disulfide in presence of KOH and ethanol, under reflux. The novel 1-substituted-phenyl-3-[2-thioxo-3-(alkylaminomethyl)-1,3,4-oxadiazol-5-yl]-β-carboline derivatives (24-29 a-c) (Mannich bases) were obtained from the reaction of 23 a-c with appropriated amines and formaldehyde. The structures of the synthesized compounds were confirmed on the basis of their spectral data (IR, MS, 1H and 13C NMR, COSY and HMQC). The compounds 23 a-c and 24-29 (a-c) were assayed for their antitumoral activity against the human cancer cell lines UACC-62 (melanoma), MCF7 (mamma), NCI/ADR (resistant mamma), 786-0 (kidney), NCI-460 (lung), PCO-3 (prostate), OVCAR (ovary) and HT29 (colon). Also, the antimicrobial activity of the synthesized compounds against the bactéria Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Sthaphylococus aureus and the fungi Candida parapsilosis, Candida tropicalis and Candida albicans were evaluted. A computational study for prediction of ADMET properties of the novel synthesized β-carbolines derivatives was performed by determination of lipophilicity, topological polar surface area (TPSA), absorption (% ABS) and simple molecular descriptors, using Lipinski's rule.