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Design, Synthesis, Antitumor Activity and Molecular Docking Study of Novel 5-Deazaalloxazine Analogs.

ABSTRACT: Protein tyrosine kinases (PTKs) are the most potential therapeutic targets for cancer. Herein, we present a sound rationale for synthesis of a series of novel 2-(methylthio), 2-(substituted alkylamino), 2-(heterocyclic substituted), 2-amino, 2,4-dioxo and 2-deoxo-5-deazaalloxazine derivatives by applying structure-based drug design (SBDD) using AutoDock 4.2. Their antitumor activities against human CCRF-HSB-2, KB, MCF-7 and HeLa have been investigated in vitro. Many 5-deazaalloxazine analogs revealed high selective activities against MCF-7 tumor cell lines (IC50: 0.17-2.17 µM) over HeLa tumor cell lines (IC50 > 100 µM). Protein kinase profiling revealed that compound 3h induced multi- targets kinase inhibition including -43% against (FAK), -40% against (CDKI) and -36% against (SCR). Moreover, the Annexin-V/PI apoptotic assay elucidate that compound 3h showed 33% and potentially 140% increase in early and late apoptosis to MCF-7 cells respectively, compared to the control. The structure-activity relationship (SAR) and molecular docking study using PTK as a target enzyme for the synthesized 7-deazaalloaxazine derivatives were investigated as potential antitumor agents. The AutoDock binding affinities of the 5-deazaalloxazine analogs into c-kit PTK (PDB code: 1t46) revealed reasonable correlations between their AutoDock binding free energy and IC50.

SUBMITTER: Mahmoud S

PROVIDER: S-EPMC7321323 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Design, Synthesis, Antitumor Activity and Molecular Docking Study of Novel 5-Deazaalloxazine Analogs.

Mahmoud Sawsan S Samaha Doaa D Mohamed Mosaad S MS Abou Taleb Nageh A NA Elsawy Mohamed A MA Nagamatsu Tomohisa T Ali Hamed I HI

Molecules (Basel, Switzerland) 20200528 11

Protein tyrosine kinases (PTKs) are the most potential therapeutic targets for cancer. Herein, we present a sound rationale for synthesis of a series of novel 2-(methylthio), 2-(substituted alkylamino), 2-(heterocyclic substituted), 2-amino, 2,4-dioxo and 2-deoxo-5-deazaalloxazine derivatives by applying structure-based drug design (SBDD) using AutoDock 4.2. Their antitumor activities against human CCRF-HSB-2, KB, MCF-7 and HeLa have been investigated in vitro. Many 5-deazaalloxazine analogs rev ...[more]

PMID: 32481639

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Project description:BackgroundMalaria remains the major health problem responsible for many mortality and morbidity in developing countries. Because of the development of resistance by Plasmodium species, searching effective antimalarial agents becomes increasingly important. Pinocembrin is a flavanone previously isolated as the most active antiplasmodial compound from the leaves of Dodonaea angustifolia. For a better understanding of the antiplasmodial activity, the synthesis of pinocembrin and a great number of analogs was undertaken.MethodsChalcones 5a-r were synthesized via Claisen-Schmidt condensation using 2,4-dibenzyloxy-6-hydroxyacetophenone and aromatic aldehydes as substrates under basic conditions. Cyclization of compounds 5a-r to the corresponding dibenzylated pinocembrin analogs 6a-r was achieved using NaOAc in EtOH under reflux. Catalytic hydrogenation using 10% Pd/C as catalyst in an H-Cube Pro was used for debenzylation to deliver 7a-l. The structures of the synthesized compounds were characterized using various physical and spectroscopic methods, including mp, UV, IR, NMR, MS and HRMS. The synthesized dibenzylated flavanones 6a-d, 6i and 7a were evaluated for their in vivo antiplasmodial activities against Plasmodium berghei infected mice. Molecular docking simulation and drug likeness properties of compounds 7a-l were assessed using AutoDock Vina and SwissADME, respectively.ResultsA series of chalcones 5a-r has been synthesized in yields ranging from 46 to 98%. Treatment of the chalcones 5a-r with NaOAc refluxing in EtOH afforded the dibenzylated pinocembrin analogs 6a-r with yields up to 54%. Deprotection of the dibenzylated pinocembrin analogs delivered the products 7a-l in yields ranging from 78 to 94%. The dibenzylated analogs of pinocembrin displayed percent inhibition of parastaemia in the range between 17.4 and 87.2% at 30 mg/kg body weight. The parastaemia inhibition of 87.2 and 55.6% was obtained on treatment of the infected mice with pinocembrin (7a) and 4'-chloro-5,7-dibenzylpinocembrin (6e), respectively. The mean survival times of those infected mice treated with these two compounds were beyond 14 days indicating that the samples suppressed P. berghei and reduced the overall pathogenic effect of the parasite. The molecular docking analysis of the chloro derivatives of pinocembrin revealed that compounds 7a-l show docking affinities ranging from - 8.1 to - 8.4 kcal/mol while it was -7.2 kcal/mol for chloroquine.ConclusionPinocembrin (7a) and 4'-chloro-5,7-dibenzyloxyflavanone (6e) displayed good antiplasmodial activity. The in silico docking simulation against P. falciparum dihydrofolate reductase-thymidylate synthase revealed that pinocembrin (7a) and its chloro analogs 7a-l showed better binding affinity compared with chloroquine that was used as a standard drug. This is in agreement with the drug-like properties of compounds 7a-l which fulfill Lipinski's rule of five with zero violations. Therefore, pinocembrin and its chloro analogs could serve as lead compounds for further antiplasmodial drug development.

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Design, Synthesis, Antitumor Activity and Molecular Docking Study of Novel 5-Deazaalloxazine Analogs.

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Design, Synthesis, Antitumor Activity and Molecular Docking Study of Novel 5-Deazaalloxazine Analogs.

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