Planejamento, síntese e avaliação de compostos quinolínicos como candidatos a fármacos para o tratamento da tuberculose

Abstract

Tuberculosis is an infectious disease contracted through contact with Mycobacterium tuberculosis (Mtb), its main causal agent in humans. It is currently the one of the leading causes of death worldwide and one of the leading causes of death due to a single pathogen, ahead of HIV infection (human immunodeficiency virus). Recently, due to efforts accomplished by health system to contain the pandemic caused by the SARS-CoV-2 virus, there has been a significant decrease in case reports, decrease in adequate treatment and public investments to contain the disease. Despite existing pharmacological treatment being relatively effective, the therapeutic regimen has low adherence and considered adverse effects. In addition, the emergence of Mtb strains resistant to existing drugs has made clinical management difficult and contributed to the maintenance of mortality rates attributed to the disease. Interestingly, the 21st century has seen the approval of new drugs for the treatment of conditions caused by resistant strains of Mtb. Bedaquiline (2012), Delamanid (2014) and Pretomanid (2019) are now novel alternatives for the tuberculosis treatment. However, possible adverse events and the report of the emergence of infections resistant to these drugs demonstrate that research to obtain innovative structures for the treatment of the disease must still be a priority. In this context, the present work followed the study of the class of 2-(quinolin-4-yloxy)acetamides as a possible therapeutic alternative for the treatment of tuberculosis. The first part of the work proposed the removal of the acetamide function in order to increase the metabolic stability of the compounds and maintain the antimycobacterial activity at submicromolar range. The molecules were synthesized in 13–97% yields. The results obtained showed that molecular simplification, with the absence of the acetamide group, can, in some cases, increase metabolic stability. However, the Minimum Inhibitory Concentration (MIC) values of these structures against the Mtb H37Rv strain were reduced. The MICs of the most effective compounds in this series ranged from 0.3 μM to 1.9 μM. The second part of the work developed a method using ultrasound energy for the synthesis of 4-alkoxy-6-methoxy-2-methylquinolines. Such compounds come from the molecular simplification proposed in the first part of the work. The new synthetic protocol provided a simple procedure (15 min) using an open vessel system that provided the products with yields ranging from 45–84% and purities ≥ 95%. The fast and accessible methodology facilitated the determination of the structure-activity relationship of the series of molecules with a reduced environmental and operational cost compared to the conventional method (18 h, 25 °C). Since the maintenance of the acetamide function linked to the quinoline ring proved to be necessary to potent activity against the bacillus, the third part of the work proposed structures containing electron-donating groups linked to this function. These groups would reduce the electrophilicity of the amide carbonyl and, concomitantly, would increase the stability of the chemical function in relation to hydrolysis reactions. The molecules were obtained in 44–88% yields. This strategy led to a structure with MIC value of 0.09 μM against the Mtb H37Rv strain. In addition, the compound showed the ability to inhibit the bacillus intracellularly and exhibited satisfactory pharmacokinetic exposure after gavage administration to mice (F = 51%). The fourth part of the present work expanded the structure-activity relationship of the designed molecules using molecular simplification (first part). Once again, the acetamide group gave way to the ketone or alkoxy group at the 4-position of the quinoline ring. The structures were obtained in 63–95% yields after stirring the alkylating agent and the heterocycle for 18 h at 25 °C. The MICs of these compounds against the Mtb H37Rv strain ranged from 0.8 μM to 16 μM. Finally, the fifth and last step synthesized quinolines containing substituents with a hydrophobic character attached to the piperidine substituent in order to increase the interaction with the possible molecular target (bC1 complex). Furthermore, the presence of benzene rings substituted in this position allowed us to evaluate the bioisosterism between the quinoline ring and the imidazo[1,2-a]pyridine ring present in the clinical candidate Telacebec. The structures were obtained in 36-96% yields and were able to inhibit the bacillus with MIC values as low as 0.02 μM. These compounds were the most effective so far obtained by the research group and comprise a select group of molecules with MIC in the nanomolar range. Therefore, the data denote that the class of quinoline compounds may provide drug candidates for the tuberculosis treatment. The results of bacillus inhibition, action against strains resistant to available drugs, selectivity, chemical and metabolic stability, solubility and permeability are promising. Thus, new results are expected to confirm that these molecules or their congeners can effectively contribute as a new alternative for the treatment of this disease.