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Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs.
J Med Chem. 1998 Jan 15; 41(2):148-56.JM

Abstract

Given the role of trypanothione in the redox defenses of pathogenic trypanosomal and leishmanial parasites, in contrast to glutathione for their mammalian hosts, selective inhibitors of trypanothione reductase are potential drug leads against trypanosomiasis and leishmaniasis. In the present study, the rational drug design approach was used to discover tricyclic neuroleptic molecular frameworks as lead structures for the development of inhibitors, selective for trypanothione reductase over host glutathione reductase. From a homology-modeled structure for trypanothione reductase, replaced in the later stages of the study by the X-ray coordinates for the enzyme from Crithidia fasciculata, a series of inhibitors based on phenothiazine was designed. These were shown to be reversible inhibitors of trypanothione reductase from Trypanosoma cruzi, linearly competitive with trypanothione as substrate and noncompetitive with NADPH, consistent with ping-pong bi bi kinetics. Analogues, synthesized to define structure-activity relationships for the active site, included N-acylpromazines, 2-substituted phenothiazines, and trisubstituted promazines. Analysis of Ki and I50 data, on the basis of calculated log P and molar refractivity values, provided evidence of a specially favored fit of small 2-substituents (especially 2-chloro and 2-trifluoromethyl), with a remote hydrophobic patch on the enzyme accessible for larger, hydrophobic 2-substituents. There was also evidence of an additional hydrophobic enzymic region available to suitable N-substituents of the promazine nucleus. Ki data also indicated that the phenothiazine nucleus can adopt more than one inhibitory orientation in its binding site. Selected compounds were tested for in vitro activity against Trypanosoma brucei, T. cruzi, and Leishmania donovani, with selective activities in the micromolar range being determined for a number of them.

Authors+Show Affiliations

Department of Pharmacy, University of Manchester, U.K.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9457238

Citation

Chan, C, et al. "Phenothiazine Inhibitors of Trypanothione Reductase as Potential Antitrypanosomal and Antileishmanial Drugs." Journal of Medicinal Chemistry, vol. 41, no. 2, 1998, pp. 148-56.
Chan C, Yin H, Garforth J, et al. Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs. J Med Chem. 1998;41(2):148-56.
Chan, C., Yin, H., Garforth, J., McKie, J. H., Jaouhari, R., Speers, P., Douglas, K. T., Rock, P. J., Yardley, V., Croft, S. L., & Fairlamb, A. H. (1998). Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs. Journal of Medicinal Chemistry, 41(2), 148-56.
Chan C, et al. Phenothiazine Inhibitors of Trypanothione Reductase as Potential Antitrypanosomal and Antileishmanial Drugs. J Med Chem. 1998 Jan 15;41(2):148-56. PubMed PMID: 9457238.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs. AU - Chan,C, AU - Yin,H, AU - Garforth,J, AU - McKie,J H, AU - Jaouhari,R, AU - Speers,P, AU - Douglas,K T, AU - Rock,P J, AU - Yardley,V, AU - Croft,S L, AU - Fairlamb,A H, PY - 1998/2/11/pubmed PY - 1998/2/11/medline PY - 1998/2/11/entrez SP - 148 EP - 56 JF - Journal of medicinal chemistry JO - J Med Chem VL - 41 IS - 2 N2 - Given the role of trypanothione in the redox defenses of pathogenic trypanosomal and leishmanial parasites, in contrast to glutathione for their mammalian hosts, selective inhibitors of trypanothione reductase are potential drug leads against trypanosomiasis and leishmaniasis. In the present study, the rational drug design approach was used to discover tricyclic neuroleptic molecular frameworks as lead structures for the development of inhibitors, selective for trypanothione reductase over host glutathione reductase. From a homology-modeled structure for trypanothione reductase, replaced in the later stages of the study by the X-ray coordinates for the enzyme from Crithidia fasciculata, a series of inhibitors based on phenothiazine was designed. These were shown to be reversible inhibitors of trypanothione reductase from Trypanosoma cruzi, linearly competitive with trypanothione as substrate and noncompetitive with NADPH, consistent with ping-pong bi bi kinetics. Analogues, synthesized to define structure-activity relationships for the active site, included N-acylpromazines, 2-substituted phenothiazines, and trisubstituted promazines. Analysis of Ki and I50 data, on the basis of calculated log P and molar refractivity values, provided evidence of a specially favored fit of small 2-substituents (especially 2-chloro and 2-trifluoromethyl), with a remote hydrophobic patch on the enzyme accessible for larger, hydrophobic 2-substituents. There was also evidence of an additional hydrophobic enzymic region available to suitable N-substituents of the promazine nucleus. Ki data also indicated that the phenothiazine nucleus can adopt more than one inhibitory orientation in its binding site. Selected compounds were tested for in vitro activity against Trypanosoma brucei, T. cruzi, and Leishmania donovani, with selective activities in the micromolar range being determined for a number of them. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9457238/Phenothiazine_inhibitors_of_trypanothione_reductase_as_potential_antitrypanosomal_and_antileishmanial_drugs_ L2 - https://doi.org/10.1021/jm960814j DB - PRIME DP - Unbound Medicine ER -