Preliminary Structure − Activity Relationships and Biological Evaluation of Novel Antitubercular Indolecarboxamide Derivatives Against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains

Tuberculosis (TB) remains one of the leading causes of mortality and morbidity worldwide, with approximately one-third of the world’s population infected with latent TB. This is further aggravated by HIV coinfection and the emergence of multidrugand extensively drug-resistant (MDR and XDR, respectively) TB; hence the quest for highly effective antitubercular drugs with novel modes of action is imperative. We report herein the discovery of an indole-2-carboxamide analogue, 3, as a highly potent antitubercular agent, and the subsequent chemical modifications aimed at establishing a preliminary body of structure−activity relationships (SARs). These efforts led to the identification of three molecules (12−14) possessing an exceptional activity in the low nanomolar range against actively replicating Mycobacterium tuberculosis, with minimum inhibitory concentration (MIC) values lower than those of the most prominent antitubercular agents currently in use. These compounds were also devoid of apparent toxicity to Vero cells. Importantly, compound 12 was found to be active against the tested XDR-TB strains and orally active in the serum inhibition titration assay. ■ INTRODUCTION TB is a highly contagious and insidious disease caused by Mycobacterium tuberculosis (M. tuberculosis) and is currently the second leading cause of mortality due to infectious disease worldwide. Despite its known etiology, TB still remains one of the most threatening health problems globally, claiming 1.4 million lives in 2011. First-line TB chemotherapy options have not changed in nearly five decades, with the most recent drug rifampin having been introduced in early 1960s. The current treatment regimen for drug susceptible M. tuberculosis requires the daily administration of first-line drugs which include ethambutol, isoniazid, pyrazinamide, and rifampin for two months followed by an additional four months of daily administration of isoniazid and rifampin. However, several factors such as inconsistent treatment, patient noncompliance, and the nonavailability of drugs during this period have contributed to the failure to achieve a cure, making the emergence of resistance an event practically unavoidable in many-resource-limited countries. Drug resistant-TB can be classified into two categories. MDR-TB is caused by infection with M. tuberculosis resistant to isoniazid and rifampin and requires 18−24 months of combination therapy with second-line drugs which are generally more toxic, expensive, and difficult to administer. XDR-TB is caused by M. tuberculosis resistant to isoniazid, rifampin, at least one fluoroquinolone, and one of the injectable antitubercular drugs such as amikacin, kanamycin, or capreomycin. The success rate for the treatment of XDR-TB is very low depending on the extent of drug resistance and whether or not the immune system of the patient is compromised. Consequently, in the development of novel antitubercular chemotherapeutics, the lack of Received: March 15, 2013 Published: April 23, 2013 Article