Further Improved Derivatives of Isoniazid with Enhanced Activity

Unmet Need
In 2015, there were approximately 10.4 million new cases of tuberculosis (TB). More than 95% of cases and deaths due to TB are found in developing countries with India, Indonesia, China, Pakistan and South Africa accounting for 60% of global TB cases. TB is an airborne disease that can be easily spread from person to person. The market for tuberculosis is expected to reach $863.9 million by 2022 with a CAGR of 8%. Current treatments last 6-9 weeks and the main anti-TB therapeutic agent is isoniazid (INH). Despite its prevalence, there is limited understanding of the improvements of INH. The proposed invention uses isotopically labeled derivatives of INH, ethionamide and related compounds as effective therapy for the treatment of mycrobacterial disease, including mycobacterium tuberculosis.
 
Technology Overview
It has been demonstrated that peroxidative activation of INH by mycobacterial enzyme KateG generates reactive species that forms adducts with NAD and NADP. This causes antibiotic action against TB. The inventors have discovered the precise reaction mechanism to form these adducts that could improve the effectiveness of INH. The proposed technology offers substitutions to alter the stability of INH acyl radical, upon anti-TB activity. The inventor suggests a heavy oxygen isotope and hydrazide substation at the acyl group of INH. These changes could in INH could be developed into highly potent drugs for TB.
 
Stage of Development
The role of hydrazide group substitution has been tested. The compounds demonstrate better activity in INH in an MIC assay in vitro.
 
Publications
N/A
 

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