A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides

Leena Keurulainen; Mikko Vahermo; Margarita Puente-Felipe; Elena Sandoval-Izquierdo; Benigno Crespo-Fernandez; Laura Guijarro-Lopez; Leticia Huertas-Valentin; Laura de las Heras-Duena; Teppo O. Leino; Antti Siiskonen; Lluis Balla-Pages; Laura M. Sanz; Pablo Castaneda-Casado; M. Belen Jimenez-Diaz; Maria S. Martinez-Martinez; Sara Viera; Paula Kiuru; Felix Calderon; Jari Yli-Kauhaluoma

doi:10.1021/acs.jmedchem.5b00114

A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides

Leena Keurulainen, Mikko Vahermo, Margarita Puente-Felipe, Elena Sandoval-Izquierdo, Benigno Crespo-Fernandez, Laura Guijarro-Lopez, Leticia Huertas-Valentin, Laura de las Heras-Duena, Teppo O. Leino, Antti Siiskonen, Lluis Balla-Pages, Laura M. Sanz, Pablo Castaneda-Casado, M. Belen Jimenez-Diaz, Maria S. Martinez-Martinez, Sara Viera, Paula Kiuru, Felix Calderon, Jari Yli-Kauhaluoma

Research output: Contribution to journal › Article › Scientific › peer-review

15 Citations (Scopus)

Abstract

Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.

Original language	English
Pages (from-to)	4573-4580
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	11
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00114
Publication status	Published - 11 Jun 2015
Externally published	Yes
Publication type	A1 Journal article-refereed

Funding

We thank Tres Cantos Open Lab Foundation (project TC045), GlaxoSmithKline, University of Helsinki, and the Academy of Finland (project no. 265481) for financial support. Dr. Leo Ghemtio and Dr. Henri Xhaard are thanked for valuable help in computational studies during the project. The CSC-IT Center for Science Ltd. (Helsinki, Finland) and the Drug Discovery and Chemical Biology Network of the Biocenter Finland are thanked for computational resources.

Keywords

PLASMODIUM-FALCIPARUM
STARTING POINTS
DE-POINTES
MALARIA
BENZIMIDAZOLES
PROLONGATION
TCAMS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acs.jmedchem.5b00114

Cite this

Keurulainen, L., Vahermo, M., Puente-Felipe, M., Sandoval-Izquierdo, E., Crespo-Fernandez, B., Guijarro-Lopez, L., Huertas-Valentin, L., de las Heras-Duena, L., Leino, T. O., Siiskonen, A., Balla-Pages, L., Sanz, L. M., Castaneda-Casado, P., Belen Jimenez-Diaz, M., Martinez-Martinez, M. S., Viera, S., Kiuru, P., Calderon, F., & Yli-Kauhaluoma, J. (2015). A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides. Journal of Medicinal Chemistry, 58(11), 4573-4580. https://doi.org/10.1021/acs.jmedchem.5b00114

@article{cead5ef731c04dc4acf594eec7dc6a34,

title = "A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides",

abstract = "Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.",

keywords = "PLASMODIUM-FALCIPARUM, STARTING POINTS, DE-POINTES, MALARIA, BENZIMIDAZOLES, PROLONGATION, TCAMS",

author = "Leena Keurulainen and Mikko Vahermo and Margarita Puente-Felipe and Elena Sandoval-Izquierdo and Benigno Crespo-Fernandez and Laura Guijarro-Lopez and Leticia Huertas-Valentin and {de las Heras-Duena}, Laura and Leino, {Teppo O.} and Antti Siiskonen and Lluis Balla-Pages and Sanz, {Laura M.} and Pablo Castaneda-Casado and {Belen Jimenez-Diaz}, M. and Martinez-Martinez, {Maria S.} and Sara Viera and Paula Kiuru and Felix Calderon and Jari Yli-Kauhaluoma",

year = "2015",

month = jun,

day = "11",

doi = "10.1021/acs.jmedchem.5b00114",

language = "English",

volume = "58",

pages = "4573--4580",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "11",

}

Keurulainen, L, Vahermo, M, Puente-Felipe, M, Sandoval-Izquierdo, E, Crespo-Fernandez, B, Guijarro-Lopez, L, Huertas-Valentin, L, de las Heras-Duena, L, Leino, TO, Siiskonen, A, Balla-Pages, L, Sanz, LM, Castaneda-Casado, P, Belen Jimenez-Diaz, M, Martinez-Martinez, MS, Viera, S, Kiuru, P, Calderon, F & Yli-Kauhaluoma, J 2015, 'A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides', Journal of Medicinal Chemistry, vol. 58, no. 11, pp. 4573-4580. https://doi.org/10.1021/acs.jmedchem.5b00114

A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides. / Keurulainen, Leena; Vahermo, Mikko; Puente-Felipe, Margarita et al.
In: Journal of Medicinal Chemistry, Vol. 58, No. 11, 11.06.2015, p. 4573-4580.

Research output: Contribution to journal › Article › Scientific › peer-review

TY - JOUR

T1 - A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials

T2 - N-[3-[(Benzimidazol-2-yl)amino]propyl]amides

AU - Keurulainen, Leena

AU - Vahermo, Mikko

AU - Puente-Felipe, Margarita

AU - Sandoval-Izquierdo, Elena

AU - Crespo-Fernandez, Benigno

AU - Guijarro-Lopez, Laura

AU - Huertas-Valentin, Leticia

AU - de las Heras-Duena, Laura

AU - Leino, Teppo O.

AU - Siiskonen, Antti

AU - Balla-Pages, Lluis

AU - Sanz, Laura M.

AU - Castaneda-Casado, Pablo

AU - Belen Jimenez-Diaz, M.

AU - Martinez-Martinez, Maria S.

AU - Viera, Sara

AU - Kiuru, Paula

AU - Calderon, Felix

AU - Yli-Kauhaluoma, Jari

PY - 2015/6/11

Y1 - 2015/6/11

N2 - Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.

AB - Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.

KW - PLASMODIUM-FALCIPARUM

KW - STARTING POINTS

KW - DE-POINTES

KW - MALARIA

KW - BENZIMIDAZOLES

KW - PROLONGATION

KW - TCAMS

U2 - 10.1021/acs.jmedchem.5b00114

DO - 10.1021/acs.jmedchem.5b00114

M3 - Article

SN - 0022-2623

VL - 58

SP - 4573

EP - 4580

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -

A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides

Abstract

Funding

Keywords

UN SDGs

Access to Document

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Cite this