Preliminary studies on ligand-based design and evaluation of new mycobacterial ATP synthase inhibitors

Background: Tuberculosis is a threat to humankind due to the development of resistance against the existing drugs, so new drugs are an absolute necessity. Neuroleptic phenothiazines were reported for antitubercular activity, but the associated antipsychotic effect restricted their antitubercular use. Objective: Novel mycobacterial ATP synthase inhibitors having structural similarity with phenothiazines were designed in an attempt to develop potent antitubercular agents with no or less side effects. Methods: The designed molecules were synthesized and screened against Mycobacterium tuberculosis H37Rv (Mtb). The compounds with strongest growth inhibition of whole Mtb (S3, S4, S9, S10, and S16) were screened for ATP synthesis inhibition using inverted membrane vesicles from Mycobacterium smegmatis, and were also screened for blood-brain barrier (BBB) permeability and mammalian cell cytotoxicity to assess the possible side effects. Results: Among all the compounds, S9 and S10 were found to be the most active (6.25 µg/mL) against Mtb and were comparable to chlorpromazine (12.5 µg/mL). Moreover, the compounds inhibited ATP synthesis at IC₅₀ of 14 and 10.4 µM, respectively. A better correlation between MIC and IC₅₀ observed, indicated that the compounds acted through mycobacterial ATP synthase inhibition. The blood-brain barrier (BBB) crossing ability of the compounds (S9, S10) was found to be less, indicating diminished CNS side effects. The compounds (S3, S4, S9, S10, and S16) were also marked safe against mammalian VERO cells, as CC₅₀ was > 102 µg/mL. Conclusion: The enhanced antitubercular activity with reduced BBB permeability exhibited by the compounds has good prospect to develop them as antitubercular drugs.