Design, synthesis and computational studies of isoniazid hybrid conjugates as potential antimycobacterial agents

Abstract

Tuberculosis (TB) is a bacterial pathogen caused by Mycobacterium tuberculosis, which generally causes pulmonary infection and is extremely pervasive within the lungs and between subjects. Pyrazinamide (PZA) and isoniazid are first-line anti-tuberculosis prodrug often used in combinational therapy with drugs like ethambutol, streptomycin and/or rifampicin. With prolonged administration of the recommended dose, harmful side effects have been reported: hepatitis, acute hypertension, thrombocytopenia, and gastrointestinal discomfort. To overcome the problem of toxicity and drug resistance, combination therapy has been used which utilizes the simultaneous administration of two or more antibiotics with independent modes of action and different biochemical targets in the bacteria. Recently, the concept of hybrid molecules has been introduced in anticipation that molecules of this type may overcome drug resistance. This multiple target strategy led to the discovery of various bio-effective hybrid molecules. We have synthesized several pyrazinoic acid hybrid conjugates with isoniazid via amino acid linkers with retention of the chiral integrity of the desired products. All the synthesized compounds were characterized by spectral studies. The details of the studies will be discussed at the conference.