Inhibitory and lytic effects of phenothiazine derivatives and related tricyclic neuroleptic compounds, on Entamoeba histolytica HK9 and HMI trophozoites

It has been shown previously that tricyclic neuroleptics like clomipramine and chlorpromazine have lethal effects on Leishmania donovani and L. major, and other studies indicate that the phenothiazine inhibitors of trypanothi one reductase are potential anti-trypanosomal and anti-leishmanial drugs, W ith this in mind and our original observation on the presence of trypanothi one in Entamoeba histolytica HK9, we examined the possible inhibitory effec ts of various phenothiazine and tricyclic derivatives on this human parasit e. We found that drugs like clomipramine (KD002), the most potent in vitro inhibitor of trypanothione reductase among 30 tricyclic compounds tested, a t 25 mu M after 24 h of culture under aerobic conditions, caused a substant ial decrease in the number of E. histolytica HK9 trophozoites, from approx, 15 x 10(6) to 5.37 x 10(6) cells, and at 100 mu M to 0.8 x 10(6) cells, A substantial inhibitory effect on cell proliferation could also be demonstra ted with metronidazol (used clinically against amoebiasis). Under similar e xperimental conditions other tricyclic and phenothiazine derivatives (OFKs) , designed originally to inhibit the trypanothione reductase of trypanosoma tides, had an inhibitory effect of 16 to 95%, For comparison, similar resul ts were obtained using clomipramine and a phenothiazine derivative (OFK006) with Trypanosoma cruzi and Crithidia luciliae, except that with the latter the inhibitory effect of clomipramine was less dramatic. Experiments compa ring two E. histolytica strains showed that normal cell proliferation under anaerobiosis was higher in strain HK9 than in HMI, which is highly virulen t, but that metronidazol and clomipramine were less effective against HMI. Two other drugs tested, diphenydramine (KD005) and a phenothiazine derivati ve (OFK008), also had significant but lower inhibitory effects on both stra ins. The inhibitory activity on cell proliferation and the lytic effects on this human parasite by the tricyclic compounds clomipramine, chlorpromazin e and others, as well as by the phenothiazine derivatives, indicate that th ey can be considered potential anti-amoebic agents.