Background: Strategies for development of anti-parasite chemotherapy involve identification of active principles of plants, investigation of drugs already licensed for other pathologies, or validat...

Trypanosoma cruzi targets for new chemotherapeutic approaches

Design strategies of oxidosqualene cyclase inhibitors: Targeting the sterol biosynthetic pathway.

Oxidosqualene cyclase from Saccharomyces cerevisiae, Trypanosoma cruzi, Pneumocystis carinii and Arabidopsis thaliana expressed in yeast: a model for the development of novel antiparasitic agents.

American Trypanosomiasis, a parasitic infection commonly named Chagas disease, affects millions of people all over Latin American countries. Presently, the World Health Organization (WHO) predicts that the number of international infected individuals extends to 7 to 8 million, assuming that more than 10,000 deaths occur annually. The transmission of the etiologic agent, Trypanosoma cruzi, through people migrating to non-endemic world nations makes it an emergent disease. The best promising targets for trypanocidal drugs may be classified into three main groups: Group I includes the main molecular targets that are considered among specific enzymes involved in the essential processes for parasite survival, principally Cruzipain, the major antigenic parasite cysteine proteinase. Group II involves biological pathways and their key specific enzymes, such as Sterol biosynthesis pathway, among others, specific antioxidant defense mechanisms, and bioenergetics ones. Group III includes the atypical organelles /structures present in the parasite relevant clinical forms, which are absent or considerably different from those present in mammals and biological processes related to them. These can be considered potential targets to develop drugs with extra effectiveness and fewer secondary effects than the currently used therapeutics. An improved distinction between the host and the parasite targets will help fight against this neglected disease.

Major Kinds of Drug Targets in Chagas Disease or American Trypanosomiasis.

Human and murine lanosterol synthases (EC 5.4.99.7) were studied as targets of a series of umbelliferone aminoalkyl derivatives previously tested as inhibitors of oxidosqualene cyclases from other eukaryotes. Tests were carried out on cell cultures of human keratinocytes and mouse 3T3 fibroblasts incubated with radiolabeled acetate, and on homogenates prepared from yeast cells expressing human lanosterol synthase, incubated with radiolabeled oxidosqualene. In cell cultures of both human keratinocytes and mouse 3T3 fibroblasts, the observed inhibition of cholesterol biosynthesis was selective for oxidosqualene cyclase. The most active compounds bear an allylmethylamino chain in position-7 of the coumarin ring. The inhibition was critically dependent on the position and length of the inhibitor side chain, as well as on the type of aminoalkyl group inserted at the end of the same chain. Molecular docking analyses, carried out to clarify details of inhibitors/enzyme interactions, proved useful to explain the ...

Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

Design, synthesis, and biological evaluation of new (2E,6E)-10-(dimethylamino)-3,7-dimethyl-2,6-decadien-1-ol ethers as inhibitors of human and Trypanosoma cruzi oxidosqualene cyclase.

New dimethylamino truncated squalene ether derivatives containing a different aromatic moiety (phenyl, naphthyl, and biphenyl) or a simple alkyl (n-hexylic) group were synthesized as inhibitors of the oxidosqualene cyclase (OSC) and of the sterol biosynthetic pathway. The activity against human OSC was compared with the activity against the OSCs of pathogenic organisms such as Pneumocystis carinii and Trypanosoma cruzi. The phenyl derivative was the most potent inhibitor of T. cruzi OSC.

Design, Synthesis, and Biological Evaluation of New (2E,6E)‐10‐(Dimethylamino)‐3,7‐dimethyl‐2,6‐decadien‐1‐ol Ethers as Inhibitors of Human and Trypanosoma cruzi Oxidosqualene Cyclase.

Emanuele Pastore

Papers

Design, synthesis, and biological evaluation of new (2E,6E)-10-(dimethylamino)-3,7-dimethyl-2,6-decadien-1-ol ethers as inhibitors of human and Trypanosoma cruzi oxidosqualene cyclase.

Design, Synthesis, and Biological Evaluation of New (2E,6E)‐10‐(Dimethylamino)‐3,7‐dimethyl‐2,6‐decadien‐1‐ol Ethers as Inhibitors of Human and Trypanosoma cruzi Oxidosqualene Cyclase.