Alkyl nitrobenzamides as potential DprE1 inhibitors for the treatment of tuberculosis

Tuberculosis (TB) remains a formidable global health challenge, with an annual reporting of approximately 10 million new cases. The escalating concern revolves around multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), which present barriers to effective disease control due to their resistance to both first-line and second-line drugs. One of the most promising new targets for TB treatment is the DprE1-DprE2 complex, with ongoing discoveries of novel inhibitors.

In prior unrelated research, our group showed that while studying benzoic acid derivatives, the nitro-substituted analogues exhibited interesting activity against Mycobacterium tuberculosis (Mtb). This motivated us to synthesize analogous amide derivatives, and our findings show substantial antimycobacterial activity, on par or even greater than known TB drugs.

Dinitrobenzamides represent a class of established DprE1 inhibitors, but its alkyl derivatives, akin to the compounds under discussion, were completely overlooked in available literature. Building upon our prior insights, which indicates that 8-carbon atom alkyl derivatives yielded the most potent compounds, we synthesized a series of amide derivatives and, indeed, our study shows 8-carbon atom alkyl amides amongst the most efficacious. This study extensively explores a series of nitro-substituted benzoic amide alkyl derivatives, elucidating the influence of the number and position of nitro-groups on their antitubercular activity. Moreover, we conducted supplementary biological and computational assays to assess the potential targeting of DprE1 by these compounds, as well as their efficacy in an infection model, all of which will be presented and discussed herein.