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      Drug Design, Development and Therapy (submit here)

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      Isatin-benzoazine molecular hybrids as potential antiproliferative agents: synthesis and in vitro pharmacological profiling


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          In continuation of our endeavor with respect to the development of potent and effective isatin-based anticancer agents, we adopted the molecular hybridization approach to design and synthesize four different sets of isatin-quinazoline ( 6a–f and 7a–e)/phthalazine ( 8a–f)/quinoxaline ( 9a–f) hybrids. The antiproliferative activity of the target hybrids was assessed towards HT-29 (colon), ZR-75 (breast) and A-549 (lung) human cancer cell lines. Hybrids 8b–d emerged as the most active antiproliferative congener in this study. Compound 8c induced apoptosis via increasing caspase 3/7 activity by about 5-fold in the A-549 human cancer cell line. In addition, it exhibited an increase in the G1 phase and a decrease in the S and G2/M phases in the cell cycle effect assay. Furthermore, it displayed an inhibitory concentration 50% value of 9.5 µM against multidrug-resistant NCI-H69AR lung cancer cell line. The hybrid 8c was also subjected to in vitro metabolic investigations through its incubation with rat liver microsomes and analysis of the resulting metabolites with the aid of liquid chromatography-mass spectrometry.

          Most cited references44

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          Molecular hybridization: a useful tool in the design of new drug prototypes.

          Molecular hybridization is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound with improved affinity and efficacy, when compared to the parent drugs. Additionally, this strategy can result in compounds presenting modified selectivity profile, different and/or dual modes of action and reduced undesired side effects. So, in this paper, we described several examples of different strategies for drug design, discovery and pharmacomodulation focused on new innovative hybrid compounds presenting analgesic, anti-inflammatory, platelet anti-aggregating, anti-infectious, anticancer, cardio- and neuroactive properties.
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            Hybrid molecules with a dual mode of action: dream or reality?

            The drug market is still dominated by small molecules, and more than 80% of the clinical development of drug candidates in the top 20 pharmaceutical firms is still based on small molecules. The high cost of developing and manufacturing "biological drugs" will contribute to leaving an open space for drugs based on cheap small molecules. Four main routes can be explored to design affordable and efficient drugs: (i) a drastic reduction of the production costs of biological drugs, (ii) a real improvement of drug discovery via "computer-assisted combinatorial methods", (iii) going back to an extensive exploration of natural products as drug sources, and (iv) drug discovery by rational drug design and bio-inspired design that hopefully includes serendipity and human inspiration. At the border between bio-inspired design and rational design, one can imagine preparation of hybrid molecules with a dual mode of action to create efficient new drugs. In this Account, hybrid molecules are defined as chemical entities with two or more structural domains having different biological functions and dual activity, indicating that a hybrid molecule acts as two distinct pharmacophores. In order to obtain new antimalarial drugs that are affordable and able to avoid the emergence of resistant strains, we developed hybrid molecules with a dual mode of action (a "double-edged sword") able to kill multiresistant strains by oral administration. These hybrid molecules, named trioxaquines, with two pharmacophores able to interact with the heme target are made with a trioxane motif covalently linked to an aminoquinoline entity. More than 100 trioxaquines have been prepared by Palumed over a period of 4 years, and in collaboration with Sanofi-Aventis, the trioxaquine PA1103-SAR116242 has been selected in January 2007 as candidate for preclinical development.
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              Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase.

              To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                09 August 2017
                : 11
                : 2333-2346
                [1 ]Department of Applied Organic Chemistry, National Research Centre, Giza
                [2 ]Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
                [3 ]Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
                [4 ]Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
                [5 ]Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Giza, Egypt
                Author notes
                Correspondence: Hatem A Abdel-Aziz, Department of Applied Organic Chemistry, National Research Centre, Dokki, Giza, PO Box 12622, Egypt, Tel +2 12 216 8624, Fax +2 23 337 0931, Email hatem_741@ 123456yahoo.com
                Mohamed I Attia, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia, Tel +966 1 467 3764, Fax +966 1 467 6220, Email mattia@ 123456ksu.edu.sa
                © 2017 Abdel-Aziz et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                isatins,hybridization approach,antiproliferative,apoptosis


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