Search Results

Now showing 1 - 3 of 3

Some of the metrics are blocked by your
consent settings
Computationally guided optimization of the antimalarial activity and physicochemical properties of 2,4-diaminopyrimidines
(2025-01-01)
Guntur, Guntur
;
Gleeson, Duangkamol
;
Anderson, Mark
;
Mutter, Nicole
;
Webster, Lauren
Plasmodium falciparum (Pf) is the most prevalent cause of malaria infections in humans. Due to the development of resistant strains, newer drugs, or drugs acting at novel targets are constantly being sought. Here, we report the design and preparation of 48 new 2,4-diaminopyrimidine derivatives targeting the Pf protein kinome. Bioinformatics methods have been used to identify the most probable target(s). Cheminformatics and molecular modelling have been used to guide the structural modifications. Our primary goal was to enhance the antimalarial activity of the series, reduce mammalian cytotoxicity, and increase aqueous solubility. The antimalarial activity of all 48 compounds has been assessed in chloroquine-resistant Pf3D7 strain and for their mammalian cytotoxicity in HepG2 cell lines. Phosphate buffer solubility, MDCK permeability, and metabolic clearance in human and rat microsomes were also assessed. Compounds 68 and 69 demonstrated good antimalarial activity (Pf IC<inf>50</inf>) of 0.05 and 0.06 μM, respectively, and good selectivity over the mammalian cell line (SI >100 fold). The compounds also demonstrated much improved aqueous solubilities of 989.7 and 1573 μg mL−1, respectively, along with moderate intrinsic clearance (∼3 mL min−1 g−1) and permeability (>60 nm s−1).
Some of the metrics are blocked by your
consent settings
Preparation, biological evaluation and QSAR analysis of urea substituted 2,4-diamino-pyrimidine anti-malarials
(2022-10-20)
Toviwek, Borvornwat
;
Riley, Jennifer
;
Mutter, Nicole
;
Anderson, Mark
;
Webster, Lauren
The synthesis and evaluation of twenty six new phenylurea substituted 2,4-diamino-pyrimidines against Plasmodium falciparum (Pf) 3D7 are reported. Compounds were prepared to improve both anti-malarial activity and selectivity of the series previously reported by our group. Additional properties have been determined to assess their potential as anti-malarial leads including; HepG2 cytotoxicity, solubility, permeability, and lipophilicity, as well as in vitro stability in human and rat microsomes. We also assess their inhibition profile against a diverse set of 10 human kinases. Molecular docking, cheminformatics and bioinformatics analyses were also undertaken. Compounds 40 demonstrated the best anti-malarial activity at Pf 3D7 (0.09 μM), good selectivity with respect to mammalian cytotoxicity (SI = 54) and low microsomal clearance. Quantitative structure activity relationship (QSAR) analyses point to lipophilicity being a key driver of improved anti-malarial activity. The most active compounds in the series suffered from high lipophilicity, poor aqueous solubility and low permeability. The results provide useful information to guide further chemistry iterations.
Some of the metrics are blocked by your
consent settings
Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials
(2021-09-15)
Toviwek, Borvornwat
;
Phuangsawai, Oraphan
;
Konsue, Adchatawut
;
Hannongbua, Supa
;
Riley, Jennifer
Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC<inf>50</inf> of 0.66 µM at the 3D7 strain and a selectivity (SI) of ~ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD<inf>7.4</inf> (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.

KMITL

Browse

Filters

Settings

Sort By

Results per page

Search Results