Novel 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity

Thuy G. Le, Abhijit Kundu, Atanu Ghoshal, Nghi H. Nguyen, Sarah Preston, Yaqing Jiao, Banfeng Ruan, Lian Xue, Fei Huang, Jennifer Keiser, Andreas Hofmann, Bill C.H. Chang, Jose Garcia-Bustos, Timothy N.C. Wells, Michael J. Palmer, Abdul Jabbar, Robin B. Gasser, Jonathan B. Baell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.

Original languageEnglish
Pages (from-to)3367-3380
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number7
DOIs
Publication statusPublished - 11 Apr 2019

Cite this

Le, Thuy G. ; Kundu, Abhijit ; Ghoshal, Atanu ; Nguyen, Nghi H. ; Preston, Sarah ; Jiao, Yaqing ; Ruan, Banfeng ; Xue, Lian ; Huang, Fei ; Keiser, Jennifer ; Hofmann, Andreas ; Chang, Bill C.H. ; Garcia-Bustos, Jose ; Wells, Timothy N.C. ; Palmer, Michael J. ; Jabbar, Abdul ; Gasser, Robin B. ; Baell, Jonathan B. / Novel 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 7. pp. 3367-3380.
@article{0a27a1effe7c43f59450a710e7f3953c,
title = "Novel 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity",
abstract = "A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.",
author = "Le, {Thuy G.} and Abhijit Kundu and Atanu Ghoshal and Nguyen, {Nghi H.} and Sarah Preston and Yaqing Jiao and Banfeng Ruan and Lian Xue and Fei Huang and Jennifer Keiser and Andreas Hofmann and Chang, {Bill C.H.} and Jose Garcia-Bustos and Wells, {Timothy N.C.} and Palmer, {Michael J.} and Abdul Jabbar and Gasser, {Robin B.} and Baell, {Jonathan B.}",
year = "2019",
month = "4",
day = "11",
doi = "10.1021/acs.jmedchem.8b01790",
language = "English",
volume = "62",
pages = "3367--3380",
journal = "Journal of Medicinal Chemistry",
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Le, TG, Kundu, A, Ghoshal, A, Nguyen, NH, Preston, S, Jiao, Y, Ruan, B, Xue, L, Huang, F, Keiser, J, Hofmann, A, Chang, BCH, Garcia-Bustos, J, Wells, TNC, Palmer, MJ, Jabbar, A, Gasser, RB & Baell, JB 2019, 'Novel 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity' Journal of Medicinal Chemistry, vol. 62, no. 7, pp. 3367-3380. https://doi.org/10.1021/acs.jmedchem.8b01790

Novel 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity. / Le, Thuy G.; Kundu, Abhijit; Ghoshal, Atanu; Nguyen, Nghi H.; Preston, Sarah; Jiao, Yaqing; Ruan, Banfeng; Xue, Lian; Huang, Fei; Keiser, Jennifer; Hofmann, Andreas; Chang, Bill C.H.; Garcia-Bustos, Jose; Wells, Timothy N.C.; Palmer, Michael J.; Jabbar, Abdul; Gasser, Robin B.; Baell, Jonathan B.

In: Journal of Medicinal Chemistry, Vol. 62, No. 7, 11.04.2019, p. 3367-3380.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Novel 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity

AU - Le, Thuy G.

AU - Kundu, Abhijit

AU - Ghoshal, Atanu

AU - Nguyen, Nghi H.

AU - Preston, Sarah

AU - Jiao, Yaqing

AU - Ruan, Banfeng

AU - Xue, Lian

AU - Huang, Fei

AU - Keiser, Jennifer

AU - Hofmann, Andreas

AU - Chang, Bill C.H.

AU - Garcia-Bustos, Jose

AU - Wells, Timothy N.C.

AU - Palmer, Michael J.

AU - Jabbar, Abdul

AU - Gasser, Robin B.

AU - Baell, Jonathan B.

PY - 2019/4/11

Y1 - 2019/4/11

N2 - A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.

AB - A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.

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U2 - 10.1021/acs.jmedchem.8b01790

DO - 10.1021/acs.jmedchem.8b01790

M3 - Article

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SP - 3367

EP - 3380

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -