Synthesis of cyclohexapeptides as antimalarial and anti-trypanosomal agents

S. Peña; C. Fagundez; A. Medeiros; M. Comini; L. Scarone; D. Sellanes; E. Manta; J. Tulla-Puche; F. Albericio; L. Stewart; V. Yardley; G. Serra

doi:10.1039/C4MD00135D

Synthesis of cyclohexapeptides as antimalarial and anti-trypanosomal agents†

S. Peña,^a C. Fagundez,^a A. Medeiros,^bc M. Comini,^b L. Scarone,^a D. Sellanes,^a E. Manta,^a J. Tulla-Puche,^de F. Albericio,^defg L. Stewart,^h V. Yardley^h and G. Serra*^a

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^a Cátedra de Química Farmacéutica, (DQO), Facultad de Química, Universidad de la República, Gral. Flores 2124, Montevideo, Uruguay
E-mail: gserra@fq.edu.uy
Fax: +598 29241906
Tel: +598 29290290

^b Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, Uruguay

^c Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay

^d Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028-Barcelona, Spain

^e Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain

^f Department of Organic Chemistry, University of Barcelona, 08028-Barcelona, Spain

^g School of Chemistry & Physics, University of KwaZulu-Natal, 4001-Durban, South Africa

^h Faculty of Infectious & Tropical Disease, LSHTM, Keppel Street, London, UK

Abstract

Cyclohexapeptide analogs of natural products were obtained in very good yields by a combination of solid-phase peptide synthesis, for the linear peptide, and solution cyclization. The activities against Plasmodium falciparum K1, Trypanosoma brucei brucei and murine macrophages (cell line J774) of these novel compounds and azolic macrocycles, previously reported by us, were evaluated. Seven macrocycles showed submicromolar activities against Plasmodium falciparum K1 and a high selectivity (SI > 125) for the parasite. In addition, two compounds displayed one digit micromolar EC₅₀ against T. brucei brucei and satisfactory selectivity (SI 82 and 95). Preliminary structure–activity relationships are presented.

MedChemComm

Synthesis of cyclohexapeptides as antimalarial and anti-trypanosomal agents†

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Synthesis of cyclohexapeptides as antimalarial and anti-trypanosomal agents

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