Anthrylphosphonate and π-conjugated acid cocrystal as a Mycobacterium tuberculosis inhibitor: Role of P=O…H interactions

Abstract

There have been continuous efforts to develop a candidate to combat Mycobacterium tuberculosis (MTB). Versatile, organic functional groups are being proved to be effective against MTB. However, there is a significant need for better candidates. Research on pharmaceutical cocrystal has made substantial demand with the improved physical and chemical properties and was treated as a new drug. The typical anti-MTB drug isoniazid was cocrystallized with pharmaceutically approved acids to promote stability and solubility, but the anti-MTB effect after the enhanced properties are not being evaluated. Thus, the cocrystal-based drug concept towards anti-MTB treatment has a significant lack of maturity. Herein, we have identified biologically active anthranylphosphonate as a cocrystal form with its π-conjugated acid and established it as a candidate against MTB (in vitro) with an effective minimal inhibitory concentration (MIC) of 1.56 µg/mL. The individual components phosphonate and acid disclosed the MIC (µg/mL) of 12.5 and 6.25 against MTB. As a replacement of the stoichiometric 1:1 cocrystal, MIC value for a different 1:1 mixture of phosphonate and acid was determined, and the result was disappointing. Moreover, the cytotoxic effect was not acceptable for this distinct 1:1 mixture. Such an outcome is quite exciting for a cocrystal approach to fight against MTB. We found an essential role of strong P=O…H interactions that possibly exist only in cocrystal solution, not in the separate 1:1 mixture. The same is evidenced by single-crystal X-ray in the solid-state and 31P/1H NMR spectral shift in the solution state.