10.1021/acs.jmedchem.8b01544.s001
Thuy G. Le
Thuy G.
Le
Abhijit Kundu
Abhijit
Kundu
Atanu Ghoshal
Atanu
Ghoshal
Nghi H. Nguyen
Nghi H.
Nguyen
Sarah Preston
Sarah
Preston
Yaqing Jiao
Yaqing
Jiao
Banfeng Ruan
Banfeng
Ruan
Lian Xue
Lian
Xue
Fei Huang
Fei
Huang
Jennifer Keiser
Jennifer
Keiser
Andreas Hofmann
Andreas
Hofmann
Bill C. H. Chang
Bill C. H.
Chang
Jose Garcia-Bustos
Jose
Garcia-Bustos
Abdul Jabbar
Abdul
Jabbar
Timothy N. C. Wells
Timothy
N. C. Wells
Michael J. Palmer
Michael J.
Palmer
Robin B. Gasser
Robin
B. Gasser
Jonathan B. Baell
Jonathan B.
Baell
Optimization of
Novel 1‑Methyl‑1<i>H</i>‑Pyrazole-5-carboxamides
Leads to High Potency Larval
Development Inhibitors of the Barber’s Pole Worm
American Chemical Society
2018
focus
analogue
Pyrazole
SAR
Strong
methyl
inhibition
LHS
compound
RHS
Pole
0.01 μ M
Methyl
section
High Potency Larval Development Inhibitors
identification
0.29 μ M
contrast
assembly
elucidate
Optimization
iterative
larvae
50 μ M
relationship
nematode Haemonchus contortus
phenotypic
1-
IC 50
concentration
epithelial cell line MCF 10A viability
modification
Medicinal chemistry optimization
-5-carboxamide
molecule
pyrazole
scaffold
2018-11-07 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Optimization_of_Novel_1_Methyl_1_i_H_i_Pyrazole-5-carboxamides_Leads_to_High_Potency_Larval_Development_Inhibitors_of_the_Barber_s_Pole_Worm/7396898
A phenotypic screen
of a diverse library of small molecules for
inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of
a 1-methyl-1<i>H</i>-pyrazole-5-carboxamide derivative with
an IC<sub>50</sub> of 0.29 μM. Medicinal chemistry optimization
targeted modifications on the left-hand side (LHS), middle section,
and right-hand side (RHS) of the scaffold in order to elucidate the
structure–activity relationship (SAR). Strong SAR allowed for
the iterative and directed assembly of a focus set of 64 analogues,
from which compound <b>60</b> was identified as the most potent
compound, inhibiting the development of the fourth larval (L4) stage
with an IC<sub>50</sub> of 0.01 μM. In contrast, only 18% inhibition
of the mammary epithelial cell line MCF10A viability was observed,
even at concentrations as high as 50 μM.