3’-Hydroxychalcones against multidrug-resistant Mycobacterium tuberculosis: Design using Topliss’ method, synthesis and bioassay

Chalcones are privileged scaffold in Medicinal Chemistry, due to their broad spectrum of bioactivities, easy and versatile synthesis.1 Among these, metochalcone and sofalcone have been marketed as choleretic and antiulcer drugs.2 As part of our continuing investigation for novel antitubercular agents, we synthesized 45 hydroxychalcones by Claisen-Schmidt reaction3, resulting in yields of 45-98%. Chalcones presented hydroxyl on rings A and B at positions ortho, meta and para. The major substituents on ring B were electron-withdrawing atoms/group (halogens, CF3, OCF3 and NO2), indicated by Topliss’ decision tree. Bioisosteric hypothesis was investigated by replacement of phenyl ring B by furanyl, thienyl, pyridinyl and naphthyl rings. Twelve hydroxychalcones substituted by electron-withdrawing and hydrophobic groups exhibited activity against H37Rv (sensitive and ATCC strain)4, demonstrating MIC values ranging from 4.6 to 14.7μM. These chalcone were selected to evaluation against human pneumocytes4. Three chalcones exhibited low toxicity IC50 > 100μM and were assayed against resistant clinical isolates. For clinical strains A (resistant to isoniazid), B (resistant to isoniazid and rifampicin) and C (resistant to isoniazid, rifampicin and moxifloxacin), 12 displayed MIC values of 39.9, 33.9 and 27.7μM, respectively. For clinical strains D (resistant to isoniazid, rifampicin and amikacin), 19 presented MIC value of 27.3μM. Additionally, bioactive 3’-hydroxychalcones were subjected to in silico analysis to predict their drugability. All compounds did not violate their Lipinski’s and Veber’s boundaries, and potent antitubercular hydroxychalcones exhibited absorption percentage ranging from 80.3 to 96.1. These values corroborated their ability to penetrate into highly hydrophobic mycolic acid layer of M. tuberculosis and blood-brain membrane, which is relevant barrier to drugs to act against tuberculous meningitis.