Amino-Substituted 3-Aryl- And 3-Heteroarylquinolines as Potential Antileishmanial Agents

Jared T. Hammill; Vitaliy M. Sviripa; Liliia M. Kril; Diana Ortiz; Corinne M. Fargo; Ho Shin Kim; Yizhe Chen; Jonah Rector; Amy L. Rice; Malgorzata A. Domagalska; Kristin L. Begley; Chunming Liu; Vivek M. Rangnekar; Jean Claude Dujardin; David S. Watt; Scott M. Landfear; R. Kiplin Guy

doi:10.1021/acs.jmedchem.1c00813

Amino-Substituted 3-Aryl- And 3-Heteroarylquinolines as Potential Antileishmanial Agents

Jared T. Hammill
, Vitaliy M. Sviripa
, Liliia M. Kril
, Diana Ortiz
, Corinne M. Fargo
, Ho Shin Kim
, Yizhe Chen
, Jonah Rector
, Amy L. Rice
, Malgorzata A. Domagalska
, Kristin L. Begley
, Chunming Liu
, Vivek M. Rangnekar
, Jean Claude Dujardin
, David S. Watt
, Scott M. Landfear
, R. Kiplin Guy

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

11 Scopus citations

Abstract

Leishmaniasis, a disease caused by protozoa of the Leishmania species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of Leishmania parasites with good selectivity relative to the host macrophages. Early lead 34 was rapidly acting and possessed good potency against L. mexicana (EC50 = 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC50 = 3.7 μM), and also blocked proliferation of Leishmania donovani parasites resistant to antimonial drugs. Finally, another early lead, 27, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.

Original language	English
Pages (from-to)	12152-12162
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	16
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00813
State	Published - Aug 26 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.

Funding

R.K.G., J.T.H., H.S.K., S.M.L., D.O. and C.F. were supported by NIH R33 AI127591 and D.S.W. was supported by the Office of the Dean of the College of Medicine, the Markey Cancer Center the Center for Pharmaceutical Research and Innovation (CPRI) in the College of Pharmacy, the College of Pharmacy NMR Center (University of Kentucky) for NMR support, and NIH P20 RR020171 from the National Institute of General Medical Sciences (to L. Hersh). We would like to thank Dr. Marco Sanchez (OHSU) for help with phenotypic characterization of parasites treated with arylquinolines. This manuscript's contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NIGMS. R.K.G., J.T.H., H.S.K., S.M.L., D.O., and C.F. were supported by NIH R33 AI127591 and D.S.W. was supported by the Office of the Dean of the College of Medicine, the Markey Cancer Center, the Center for Pharmaceutical Research and Innovation (CPRI) in the College of Pharmacy, the College of Pharmacy NMR Center (University of Kentucky) for NMR support, and NIH P20 RR020171 from the National Institute of General Medical Sciences (to L. Hersh). We would like to thank Dr. Marco Sanchez (OHSU) for help with phenotypic characterization of parasites treated with arylquinolines. This manuscript’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NIGMS.

Funders	Funder number
Center for Pharmaceutical Research and Innovation
Markey Cancer Center the Center for Pharmaceutical Research and Innovation
National Institutes of Health (NIH)	R33 AI127591
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences
National Center for Research Resources	P20RR020171
University of Kentucky Markey Comprehensive Cancer Center
Central Power Research Institute	P20 RR020171

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.1c00813

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Hammill, J. T., Sviripa, V. M., Kril, L. M., Ortiz, D., Fargo, C. M., Kim, H. S., Chen, Y., Rector, J., Rice, A. L., Domagalska, M. A., Begley, K. L., Liu, C., Rangnekar, V. M., Dujardin, J. C., Watt, D. S., Landfear, S. M., & Guy, R. K. (2021). Amino-Substituted 3-Aryl- And 3-Heteroarylquinolines as Potential Antileishmanial Agents. Journal of Medicinal Chemistry, 64(16), 12152-12162. https://doi.org/10.1021/acs.jmedchem.1c00813

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title = "Amino-Substituted 3-Aryl- And 3-Heteroarylquinolines as Potential Antileishmanial Agents",

abstract = "Leishmaniasis, a disease caused by protozoa of the Leishmania species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of Leishmania parasites with good selectivity relative to the host macrophages. Early lead 34 was rapidly acting and possessed good potency against L. mexicana (EC50 = 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC50 = 3.7 μM), and also blocked proliferation of Leishmania donovani parasites resistant to antimonial drugs. Finally, another early lead, 27, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.",

author = "Hammill, \{Jared T.\} and Sviripa, \{Vitaliy M.\} and Kril, \{Liliia M.\} and Diana Ortiz and Fargo, \{Corinne M.\} and Kim, \{Ho Shin\} and Yizhe Chen and Jonah Rector and Rice, \{Amy L.\} and Domagalska, \{Malgorzata A.\} and Begley, \{Kristin L.\} and Chunming Liu and Rangnekar, \{Vivek M.\} and Dujardin, \{Jean Claude\} and Watt, \{David S.\} and Landfear, \{Scott M.\} and Guy, \{R. Kiplin\}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society.",

year = "2021",

month = aug,

day = "26",

doi = "10.1021/acs.jmedchem.1c00813",

language = "English",

volume = "64",

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Hammill, JT, Sviripa, VM, Kril, LM, Ortiz, D, Fargo, CM, Kim, HS, Chen, Y, Rector, J, Rice, AL, Domagalska, MA, Begley, KL, Liu, C , Rangnekar, VM, Dujardin, JC, Watt, DS, Landfear, SM & Guy, RK 2021, 'Amino-Substituted 3-Aryl- And 3-Heteroarylquinolines as Potential Antileishmanial Agents', Journal of Medicinal Chemistry, vol. 64, no. 16, pp. 12152-12162. https://doi.org/10.1021/acs.jmedchem.1c00813

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T1 - Amino-Substituted 3-Aryl- And 3-Heteroarylquinolines as Potential Antileishmanial Agents

AU - Hammill, Jared T.

AU - Sviripa, Vitaliy M.

AU - Kril, Liliia M.

AU - Ortiz, Diana

AU - Fargo, Corinne M.

AU - Kim, Ho Shin

AU - Chen, Yizhe

AU - Rector, Jonah

AU - Rice, Amy L.

AU - Domagalska, Malgorzata A.

AU - Begley, Kristin L.

AU - Liu, Chunming

AU - Rangnekar, Vivek M.

AU - Dujardin, Jean Claude

AU - Watt, David S.

AU - Landfear, Scott M.

AU - Guy, R. Kiplin

PY - 2021/8/26

Y1 - 2021/8/26

N2 - Leishmaniasis, a disease caused by protozoa of the Leishmania species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of Leishmania parasites with good selectivity relative to the host macrophages. Early lead 34 was rapidly acting and possessed good potency against L. mexicana (EC50 = 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC50 = 3.7 μM), and also blocked proliferation of Leishmania donovani parasites resistant to antimonial drugs. Finally, another early lead, 27, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.

AB - Leishmaniasis, a disease caused by protozoa of the Leishmania species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of Leishmania parasites with good selectivity relative to the host macrophages. Early lead 34 was rapidly acting and possessed good potency against L. mexicana (EC50 = 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC50 = 3.7 μM), and also blocked proliferation of Leishmania donovani parasites resistant to antimonial drugs. Finally, another early lead, 27, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.

UR - https://www.scopus.com/pages/publications/85113826716

UR - https://www.scopus.com/pages/publications/85113826716#tab=citedBy

U2 - 10.1021/acs.jmedchem.1c00813

DO - 10.1021/acs.jmedchem.1c00813

M3 - Article

C2 - 34355566

AN - SCOPUS:85113826716

SN - 0022-2623

VL - 64

SP - 12152

EP - 12162

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 16

ER -

Amino-Substituted 3-Aryl- And 3-Heteroarylquinolines as Potential Antileishmanial Agents

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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