| Full text | |
| Author(s): Show less - |
Tavares, Mauricio T.
;
Krueger, Arne
;
Yan, Sun L. Rei
;
Waitman, Karoline B.
;
Gomes, Vinicius M.
;
de Oliveira, Daffiny Sumam
;
Paz, Franciarli
;
Hilscher, Sebastian
;
Schutkowski, Mike
;
Sippl, Wolfgang
;
Ruiz, Claudia
;
Toledo, Monica F. Z. J.
;
Hassimotto, Neuza M. A.
;
Machado-Neto, Joo A.
;
Poso, Antti
;
Cameron, Michael D.
;
Bannister, Thomas D.
;
Palmisano, Giuseppe
;
Wrenger, Carsten
;
Kronenberger, Thales
;
Parise-Filho, Roberto
Total Authors: 21
|
| Document type: | Journal article |
| Source: | SCIENTIFIC REPORTS; v. 13, n. 1, p. 20-pg., 2023-11-30. |
| Abstract | |
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 mu M in the phenotypic screening on Pf3D7 and 0.8 mu M 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. (AU) | |
| FAPESP's process: | 18/08820-0 - Nanoparticle-assisted drug delivery of Vitamin B6 pathway inhibitors in malaria |
| Grantee: | Arne Kruger |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 18/10150-3 - Understanding the cross-talk between SUMOylation and oxidative stress in Plasmodium falciparum |
| Grantee: | Daffiny Sumam de Oliveira |
| Support Opportunities: | Scholarships in Brazil - Scientific Initiation |
| FAPESP's process: | 20/04923-0 - SARS-CoV-2 glycosylation: a blueprint structural insight for understanding COVID-19 pathogenesis |
| Grantee: | Giuseppe Palmisano |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 21/00124-8 - Analysis of the SUMOylation of Plasmodium falciparum proteins during oxidative stress in erythrocytes with glucose-6-phosphate dehydrogenase deficiency |
| Grantee: | Daffiny Sumam de Oliveira |
| Support Opportunities: | Scholarships in Brazil - Master |
| FAPESP's process: | 18/18257-1 - Multi-user equipment approved in grant 14/06863-3: HPLC system configured for analysis of carbohydrates, amino acidis, peptides and glycoproteins |
| Grantee: | Giuseppe Palmisano |
| Support Opportunities: | Multi-user Equipment Program |
| FAPESP's process: | 21/08260-8 - Design, synthesis and biological evaluation of hybrid inhibitors of phosphoinositide 3-kinases and histone deacetylase 6 for the treatment of hematologic malignancies |
| Grantee: | Roberto Parise Filho |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 15/26722-8 - Drug discovery against human infectious diseases |
| Grantee: | Carsten Wrenger |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 18/15549-1 - Post-translational modifications in Chagas Disease biological processes and diagnostics: novel methodological approaches and biological applications |
| Grantee: | Giuseppe Palmisano |
| Support Opportunities: | Research Grants - Young Investigators Grants - Phase 2 |
| FAPESP's process: | 22/12468-6 - Synthesis and biological evaluation of hybrid inhibitors for the treatment of hematologic malignancies |
| Grantee: | Vinícius Albuquerque Moreira de Souza |
| Support Opportunities: | Scholarships in Brazil - Scientific Initiation |
| FAPESP's process: | 17/26358-0 - Dissection of the lipoic acid metabolism as druggable target in Malaria |
| Grantee: | Sun Liu Rei Yan |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 21/11606-3 - Investigation of the antineoplastic effects of novel PIP4K2 and HDAC inhibitors in hematologic malignancies |
| Grantee: | João Agostinho Machado Neto |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 17/03966-4 - Targeting lipoic acid salvage and biosynthesis pathways in MRSA |
| Grantee: | Carsten Wrenger |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 22/07275-4 - Design of potential new phosphoinositide 3-kinases and histone deacetylase 6 hybrid inhibitors for cancer treatment |
| Grantee: | Karoline de Barros Waitman |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |