Title:Preliminary Studies on Ligand-based Design and Evaluation of New Mycobacterial ATP Synthase Inhibitors
Volume: 13
Issue: 1
Author(s): Satheeshkumar Sellamuthu, Amer H. Asseri, Hojjat Ghasemi Goojani, Gopal Nath and Sushil K. Singh*
Affiliation:
- Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, U.P.,India
Keywords:
Antitubercular drugs, ATP synthase, cytotoxicity, blood-brain barrier permeability, drug
synthesis.
Abstract: 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 bloodbrain
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.
