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Keywords = purine bioisosteres

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9 pages, 1886 KiB  
Proceeding Paper
Modeling the Quantitative Structure–Activity Relationships of 1,2,4-Triazolo[1,5-a]pyrimidin-7-amine Analogs in the Inhibition of Plasmodium falciparum
by Inalegwu S. Apeh, Thecla O. Ayoka, Charles O. Nnadi and Wilfred O. Obonga
Eng. Proc. 2025, 87(1), 52; https://doi.org/10.3390/engproc2025087052 - 21 Apr 2025
Viewed by 725
Abstract
Triazolopyrimidine and its analogs represent an important scaffold in medicinal chemistry research. The heterocycle of 1,2,4-triazolo[1,5-a] pyrimidine (1,2,4-TAP) serves as a bioisostere candidate for purine scaffolds, N-acetylated lysine, and carboxylic acid. This study modeled the quantitative structure–activity relationship (QSAR) of 125 congeners of [...] Read more.
Triazolopyrimidine and its analogs represent an important scaffold in medicinal chemistry research. The heterocycle of 1,2,4-triazolo[1,5-a] pyrimidine (1,2,4-TAP) serves as a bioisostere candidate for purine scaffolds, N-acetylated lysine, and carboxylic acid. This study modeled the quantitative structure–activity relationship (QSAR) of 125 congeners of 1,2,4-TAP from the ChEMBL database in the inhibition of Plasmodium falciparum using six machine learning algorithms. The most significant features among 306 molecular descriptors, including one molecular outlier, were selected using recursive feature elimination. A ratio of 20% was used to split the x- and y-matrices into 99 training and 24 test compounds. The regression models were built using machine learning sci-kit-learn algorithms (multiple linear regression (MLR), k-nearest neighbours (kNN), support vector regressor (SVR), random forest regressor (RFR) RIDGE regression, and LASSO). Model performance was evaluated using the coefficient of determination (R2), mean squared error (MSE), mean absolute error (MAE), root mean squared error (RMSE), p-values, F-statistic, and variance inflation factor (VIF). Five significant variables were considered in constructing the model (p < 0.05) with the following regression equation: pIC50 = 5.90 − 0.71npr1 − 1.52pmi3 + 0.88slogP − 0.57vsurf-CW2 + 1.11vsurf-W2. On five-fold cross-validation, three algorithms—kNN (MSE = 0.46, R2 = 0.54, MAE = 0.54, RMSE = 0.68), SVR (MSE = 0.33, R2 = 0.67, MAE = 0.46, RMSE = 0.57), and RFR (MSE = 0.43, R2 = 0.58, MAE = 0.51, RMSE = 0.66)—showed strong robustness, efficiency, and reliability in predicting the pIC50 of 1,2,4-triazolo[1,5-a]pyrimidine. The models provided useful data on the functionalities necessary for developing more potent 1,2,4-TAP analogs as anti-malarial agents. Full article
(This article belongs to the Proceedings of The 5th International Electronic Conference on Applied Sciences)
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36 pages, 13267 KiB  
Article
Synthesis, Antiproliferative Activity, and ADME Profiling of Novel Racemic and Optically Pure Aryl-Substituted Purines and Purine Bioisosteres
by Martina Piškor, Astrid Milić, Sanja Koštrun, Maja Majerić Elenkov, Petra Grbčić, Sandra Kraljević Pavelić, Krešimir Pavelić and Silvana Raić-Malić
Biomolecules 2025, 15(3), 351; https://doi.org/10.3390/biom15030351 - 28 Feb 2025
Viewed by 1003
Abstract
The aim of this study was to synthesize new racemic and optically pure aryl-substituted purine bioisosteres using ultrasound-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Regioselective synthesis of α-azido alcohols was applied to afford heterocycles with a 2-hydroxyeth-1-yl linker. Catalytic asymmetric synthesis using halohydrin dehalogenase in [...] Read more.
The aim of this study was to synthesize new racemic and optically pure aryl-substituted purine bioisosteres using ultrasound-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Regioselective synthesis of α-azido alcohols was applied to afford heterocycles with a 2-hydroxyeth-1-yl linker. Catalytic asymmetric synthesis using halohydrin dehalogenase in the ring-opening of epoxides gave enantioenriched azido alcohols, which subsequently afforded R- and S-enantiomers of purine and pyrrolo[2,3-d]pyrimidines with a 1-hydroxyeth-2-yl linker. The newly synthesized compounds were evaluated in vitro for their antiproliferative activity against four malignant tumor cell lines. The influence of regioisomerism and the stereochemistry of the hydroxyethyl group, as well as a N-heterocyclic scaffold linked to the aryl moiety on cytostatic activity was evaluated. Of all the compounds tested, purine 40a and pyrrolo[2,3-d]pyrimidine 45a derivatives with p-trifluoromethyl-substituted aryl connected to 1,2,3-triazole via a 2-hydroxyeth-1-yl spacer showed promising submicromolar antiproliferative activity. In addition, compound 45a exhibited selectivity towards the tumor cell line, with a selectivity index (SI) of 40, moderate clearance, and good membrane permeability. Full article
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1 pages, 184 KiB  
Abstract
Thiazolopyrimidine as a Promising Anticancer Pharmacophore: In Silico Drug Design, Molecular Docking and ADMET Prediction Studies
by Omar A. El-Khouly, Dina I. A. Othman, Amany S. Mostafa and Mohammed A. M. Massoud
Med. Sci. Forum 2022, 14(1), 4; https://doi.org/10.3390/ECMC2022-13313 - 1 Nov 2022
Viewed by 1080
Abstract
Thiazolopyrimidines are well known to be designed to act as bio-isosteric analogues of purine nucleus. They proved to show a wide range of biological activities, such as anticancer, anti-inflammatory, antifungal, antiviral and antitubercular activity. In this study, a literature survey was thoroughly performed [...] Read more.
Thiazolopyrimidines are well known to be designed to act as bio-isosteric analogues of purine nucleus. They proved to show a wide range of biological activities, such as anticancer, anti-inflammatory, antifungal, antiviral and antitubercular activity. In this study, a literature survey was thoroughly performed to elect the most active thiazolopyrimidine-containing scaffolds, acting as anticancer agents, to be subjected to extensive computational studies in order to explore the possible credible mode of their anticancer activity. First, drug-likeness was investigated for the most active derivatives, followed by molecular docking study against Cyclin-dependent kinases (CDK), Vascular endothelial growth factor receptor (VEGFR) and Phosphoinositide 3-kinases (PI3K) enzymes in order to assess their binding energy and propose the mode of action. Next, contact preference and surface mapping studies were carried out to explain the presence of remarkable affinity of certain analogues towards a specific enzyme, in addition to providing more information about their activity. Finally, physicochemical properties, Lipinski’s rule of five and ADMET prediction studies were applied to predict the best route of administration and to suggest the pharmacokinetics of the most promising candidates. Full article
(This article belongs to the Proceedings of The 8th International Electronic Conference on Medicinal Chemistry)
19 pages, 4524 KiB  
Article
Design, Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines
by Eman M. Othman, Amany A. Bekhit, Mohamed A. Anany, Thomas Dandekar, Hanan M. Ragab and Ahmed Wahid
Molecules 2021, 26(10), 2961; https://doi.org/10.3390/molecules26102961 - 16 May 2021
Cited by 10 | Viewed by 3179
Abstract
The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were [...] Read more.
The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC50 values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells. Full article
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