Design and synthesis of indolopyridone hybrids as new antituberculosis agents. (December 2017) - Rather, Muzafar Ahmad
Abstract: Tuberculosis continues to be the most dangerous infectious disease globally and need for development of new therapies is of utmost importance. In this study we describe the rationale design for synthesis using molecular hybridization and subsequent in-vitro antimycobacterial activity of various indolo-pyridone hybrid molecules against Mycobacterium tuberculosis H37Rv. A total of 16 indolo-pyridone hybrid molecules were synthesized with 85–90% yields and characterized by various spectroscopic techniques. Four compounds were ineffective with MIC >256 μg/ml (highest concentration tested), six exhibited poor activity with MIC > 100 μg/ml, four showed moderate activity with MIC > 50 μg/ml and two had notable anti-TB activity with MIC values 32 μg/ml. Interestingly the last two compounds were observed equally effective against drug susceptible and various drug resistant strains including multidrug-resistant (MDR) strains, thereby clearly demonstrating their potential against MDR-TB. Our results showed that un-substituted aryl rings posses better antituberculosis activity than those having any kind of substitution and derivatives with small sized electron withdrawing groups in aryl ring exhibited activity while bigger groups lead to considerable loss in activity. The results of this study open up a new door for further SAR guided synthesis on one hand and on the other hand provide a promising opportunity that may lead to the discovery of a new class of antituberculosis agents. Highlights: Design and synthesis of indolo-pyridone hybrid molecules using molecular hybridization. Evaluation of these hybrid molecules against Mycobacterium tuberculosis H37Rv. Our results crystal clearly prove the successful synthesis of indolo-pyridone hybrids with excellent yields along with their antituberculosis activity. Further this study opens up a new door for SAR guided synthesis of newer indolo-pyridone hybrids as better leads for new generation of anti-tuberculosis agents.