“Síntese de derivados do 2-mercaptobenzotiazol, do 2mercaptobenzimidazol, da isoniazida e da etionamida, candidatos a novos agentes antimicrobianos” e “Estudos visando a síntese da alloenduracididina”

Abstract

The present work explored, in a first part, the synthesis of 2-mercaptobenzothiazole, 2-mercaptobenzimidazole and isoniazid derivatives condensed with carbohydrates, and the preparation of ethionamide analogues linked to amino alcohols, all potential antimicrobial agents. In a second chapter was realized a synthetic study aimed at the obtention of the nonproteinogenic α-amino acid alloenduracidine. The first part of chapter 1 relates of the synthesis and evaluation of antimicrobial properties of 2-mercaptobenzothiazole and 2-mercaptobenzimidazole derivatives condensed with carbohydrates. Ten compounds were synthesized: four derivatives of 2mercaptobenzothiazole, three derivatives of 2-mercaptobenzimidazole and three polyhydroxylated derivatives, in satisfactory yields (47-85%). Compounds 15, 17 and 20 were submitted for evaluation of antibacterial and antifungical properties at Faculdade de Farmácia e Bioquímica da UFJF. The results showed that only one derivative of 2mercaptobenzimidazole (compound 20) displayed antibacterial activity against Staphylococcus aureus with a MIC value equal to 145 µg/mL. Benzothiazole derivatives 15 and 17 were also tested against Mycobacterium tuberculosis “in vitro” at Laboratório de Bacteriologia (IPEC) of FioCruz-RJ. However, these compounds did not appear active against this microorganism. The second part of chapter 1 is aimed at the synthesis and evaluation of antitubercular activity of 13 derivatives of isoniazid (26-38), obtained in yields (20-75%), and 5 new ethionamide derivatives (44-48), obtained in low to moderate yields (20-60%). Among the analogues of ethionamide, the structure of compound 46 could be confirmed by X-ray diffraction. Analogues of INH were tested for their antibacterial activity against M. tuberculosis H37Rv (ATCC 27294) using the MABA method at IPEC-FioCruz-RJ. Several compounds exhibited activity between 0.31-3.12 µg/mL against these bacteria when compared to first choice drugs isoniazid and rifampicin. The results obtained suggest that the isoniazid derivatives synthesized in this work provide important information for the obtention of more active compounds useful for the treatment of tuberculosis. The derivatives of ethionamide synthetized are also being evaluated for their antitubercular properties.

ix As part of a Ph.D traineeship, the chapter 2 of this work describes work performed in France concerning the development of a methodology for the preparation of the non proteinogenic α-amino acid alloenduracidine. During this project three methodologies and two synthetic strategies were tested for the obtention of this amino acid. The methodologies developed permitted the preparation of compound 150a from ethyl N-Boc-(R)-allylglycinate in eight steps using the Sharpless asymmetric dihydroxylation method. Optimization of the purification procedure for compound 150a must still be performed in order to allow its complete characterization. The configuration of the asymmetric centre C-4 of 150a still remains unknown. Determination of this configuration will allow us to confirm whether if the obtained amino acid 150a is alloenduracidine (2R,4R) or its isomer (2R,4S). Application of the methodology developed during the course of this study to appropriate substrates will also allow the preparation of other naturally-occuring α-amino acids containing the guanidine function.