TY - JOUR
T1 - 1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors
AU - Tavares, Maurício T.
AU - Krüger, Arne
AU - Yan, Sun L. Rei
AU - Waitman, Karoline B.
AU - Gomes, Vinícius M.
AU - de Oliveira, Daffiny Sumam
AU - Paz, Franciarli
AU - Hilscher, Sebastian
AU - Schutkowski, Mike
AU - Sippl, Wolfgang
AU - Ruiz, Claudia
AU - Toledo, Mônica F. Z. J.
AU - Hassimotto, Neuza M. A.
AU - Machado-Neto, João A.
AU - Poso, Antti
AU - Cameron, Michael D.
AU - Bannister, Thomas D.
AU - Palmisano, Giuseppe
AU - Wrenger, Carsten
AU - Kronenberger, Thales
AU - Parise-Filho, Roberto
N1 - Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2023/11/29
Y1 - 2023/11/29
N2 - We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a–d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.
AB - We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a–d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.
UR - http://www.scopus.com/inward/record.url?scp=85178244547&partnerID=8YFLogxK
U2 - 10.1038/s41598-023-47959-z
DO - 10.1038/s41598-023-47959-z
M3 - Article
C2 - 38030668
AN - SCOPUS:85178244547
SN - 2045-2322
VL - 13
SP - 1
EP - 20
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 21006
ER -