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Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials
(2021-09-15)
Toviwek, Borvornwat
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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.
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Synthesis, plasmodium falciparum inhibitory activity, cytotoxicity and solubility of n2,n4-disubstituted quinazoline-2,4-diamines
(2019-01-01)
Pobsuk, Nattakarn
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Suphakun, Praphasri
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Hannongbua, Supa
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Nantasenamat, Chanin
;
Choowongkomon, Kiattawee
Background: Despite the development of extensive control strategies and treatment options, approximately 200 million malaria cases, leading to approximately 450,000 deaths, were reported in 2015. Due to issue of disease resistance, additional drug development efforts are needed to produce new, more effective treatments. Quinazoline-2,4-diamines were identified as anti-parasitic compounds over three decades ago and have remained of interest to date in industry and academia. Objective: An anti-malarial SAR evaluation of previously unreported N2,N4-disubstituted quina-zoline-2,4-diamines have been undertaken in this study. We have synthesized and evaluated new derivatives against P. falciparum in our attempt to better characterize their biological activity and overall physical properties. Method: The synthesis of N2,N4-disubstituted quinazoline-2,4-diamines inhibitors is reported along with activities in a radioactive labeled hypoxanthine incorporation assay against the f Plasmodium falciparum (Pf.) K1 strain. In addition, cytotoxicity was determined in the A549 and Vero cell lines using an MTT based. The aqueous solubility of key compounds was assessed at pH 7.4 using a shake flask-based approach. Results: We identified compounds 1 and 6p as sub µM inhibitors of P. falciparum, having equivalent anti-malarial activity to Chloroquine. Compounds 1 and 6m are low µM inhibitors of P. falciparum with improved cytotoxicity profiles. Compound 6m displayed the best balance between P. falciparum Inhibitory activity (2 µM) and cytotoxicity, displaying >49 fold selectivity over A549 and Vero cell lines. Conclusion: Twenty one N2,N4-Disubstituted Quinazoline-2,4-diamines have been prepared in our group and characterized in terms of their antimalarial activity, cytotoxicity and physical properties. Compounds with good activity and reasonable selectivity over mammalian cell lines have been identified. SAR analyses suggest further exploration is are necessary to improve the balance of P. falciparum Inhibitory activity, cytotoxicity and solubility.
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Classification of in Vitro Blood Stages of Plasmodium Falciparum Based on Fuzzy Inference System
(2018-08-06)
Tantisatirapong, Suchada
;
Phothisonothai, Montri
This paper proposes the automated texture based classification of Malaria parasites in Giemsa-stained thin blood film images based on fuzzy inference system (FIS). The proposed expert and knowledge based framework includes the segmentation, feature extraction and classification of erythrocytes. First-order statistical analysis includes mean, standard deviation, skewness and kurtosis have been proposed as input parameters of FIS. The effectiveness of classifier is compared to find appropriate parame- ters for classification of normal cells and infected cells, both ring and trophozoite stages. The proposed method can provide 96.28% accuracy rate for binary classification of normal and infected cells. The results also yield 97.55% accuracy for ring stage classification, and 98.54% accuracy for trophozoite stage classification.
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Automated detection of plasmodium falciparum from Giemsa-stained thin blood films
(2016-03-23)
Preedanan, Wongsakorn
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Phothisonothai, Montri
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Senavongse, Wongwit
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Tantisatirapong, Suchada
This paper investigates automated detection of malaria parasites in images of Giemsa-stained thin blood films. We aim to determine parasitemia based on automatic segmentation, feature extraction and classification methods. Segmentation relies on adaptive thresholding and watershed methods. Statistical features are then computed for each cell and classified using SVM binary classifier. Accuracy of classification is validated based on the leave-one-out cross-validation technique. This processing pipeline is applied on total 15 images of Giemsa-stained thin blood films and yields 92.71% sensitivity, 97.35% specificity and 97.17% accuracy.
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Mathematical model of Plasmodium Vivax and Plasmodium falciparum malaria
(2009-09-30)
Pongsumpun, P.
;
Tang, I. M.
Malaria is transmitted to the person by the biting of infectious Anopheles mosquitoes. This infectious disease caused by the parasite genus Plasmodium. Four species of this parasite cause human malaria, namely, Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale and Plasmodium malariae. The difference between P.vivax and P. falciparum is that a person suffering from P. vivax infection can suffer relapses of the disease. This is due the parasite being able to remain dormant in the liver of the cases where it is able to re-infect the case after a passage of time. During this stage, the case is classified as being in the dormant class. The model to describe the transmission between falciparum and vivax malaria consists of a human population divided into four classes, the susceptible, the infectious, the dormant and the recovered classes. The vector population is separated into two classes, the susceptible and infectious classes. We analyze our model by using standard dynamic modeling method. Two stable equilibrium states, a disease free state E<inf>0</inf> and an endemic state E<inf>1</inf>, are found to be possible. It is found that the E<inf>0</inf> state is stable when a basic reproductive number R<inf>0</inf> is less than one. If R<inf>0</inf> is greater than one, the endemic state E<inf>1</inf> is stable. The conditions for the local stability of each equilibrium state are established. The numerical simulations are shown to confirm the results.

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