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^*

^*Tämän työn vastaava kirjoittaja

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

18 Sitaatiot (Scopus)

Abstrakti

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.

Alkuperäiskieli	Englanti
Sivut	4573-4580
Sivumäärä	8
Julkaisu	Journal of Medicinal Chemistry
Vuosikerta	58
Numero	11
DOI - pysyväislinkit	https://doi.org/10.1021/acs.jmedchem.5b00114
Tila	Julkaistu - 11 kesäk. 2015
Julkaistu ulkoisesti	Kyllä
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

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.

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10.1021/acs.jmedchem.5b00114

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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, Vuosikerta 58, Nro 11, Sivut 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.
julkaisussa: Journal of Medicinal Chemistry, Vuosikerta 58, Nro 11, 11.06.2015, s. 4573-4580.

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

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

Abstrakti

Rahoitus

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