STRUCTURE-ANTITUBERCULAR ACTIVITY RELATIONSHIP OF PHENOTHIAZINE-TYPE CALMODULIN ANTAGONISTS

Six neuroleptic (antipsychotic) phenothiazine derivatives which are calmodulin antagonists were tested for their activity against Mycobacterium tuberculosis H(37)R(v) in order to understand their structure-antitubercular activity relationship. Out of the six derivatives tested (trifluoperazine, chlorpromazine, triflupromazine, thioridazine, acetopromazine and fluphenazine), trifluoperazine appears to be a more potent antitubercular drug than others with a minimum inhibitory concentration (MIG) of 5 mu g/ml. Chlorpromazine, triflupromazine and thioridazine are also active but less potent and have a higher MIC of 20 mu g/ml. Acetopromazine and fluphenazine could not completely inhibit the growth even at a high concentration of 20 mu g/ml. These results indicate that a methylpiperazinylpropyl group attached to the nitrogen (position 10) atom and trifluoromethyl group at the second carbon confer antitubercular activity to the phenothiazine molecule. It is suggested that trifluoperazine or one of its derivatives could be useful as one of the drugs in the multi-drug regimen for the treatment of tuberculosis with psychotic problems or vice versa.