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      Design, synthesis, heme binding and density functional theory studies of isoindoline-dione-4-aminoquinolines as potential antiplasmodials

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          Abstract

          Aim:

          WHO Malaria report 2017 estimated 216 million cases of malaria and 445,000 deaths worldwide, with 91% of deaths affecting the African region.

          Results/methodology:

          Microwave promoted the synthesis of cycloalkyl amine substituted isoindoline-1,3-dione-4-aminoquinolines was urbanized for evaluating their antiplasmodial activities. Compound with the optimum combination of propyl chain length and hydroxyethyl piperazine proved to be the most potent among the synthesized scaffolds against chloroquine-resistant W2 strain of Plasmodium falciparum with an IC 50 value of 0.006 μM. Heme-binding along with density functional theory studies were further carried out in order to delineate the mechanism of action of the most active compound.

          Conclusion:

          The synthesized scaffold can act as a therapeutic template for further synthetic modifications toward the search for a new antimalarial agent.

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          Most cited references28

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          Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination.

          Teun Bousema, Chris Drakeley (2011)
          Malaria remains a major cause of morbidity and mortality in the tropics, with Plasmodium falciparum responsible for the majority of the disease burden and P. vivax being the geographically most widely distributed cause of malaria. Gametocytes are the sexual-stage parasites that infect Anopheles mosquitoes and mediate the onward transmission of the disease. Gametocytes are poorly studied despite this crucial role, but with a recent resurgence of interest in malaria elimination, the study of gametocytes is in vogue. This review highlights the current state of knowledge with regard to the development and longevity of P. falciparum and P. vivax gametocytes in the human host and the factors influencing their distribution within endemic populations. The evidence for immune responses, antimalarial drugs, and drug resistance influencing infectiousness to mosquitoes is reviewed. We discuss how the application of molecular techniques has led to the identification of submicroscopic gametocyte carriage and to a reassessment of the human infectious reservoir. These components are drawn together to show how control measures that aim to reduce malaria transmission, such as mass drug administration and a transmission-blocking vaccine, might better be deployed.
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            Hybrid molecules with a dual mode of action: dream or reality?

            Bernard Meunier (2008)
            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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              Medical need, scientific opportunity and the drive for antimalarial drugs.

              Robert Ridley (2002)
              Continued and sustainable improvements in antimalarial medicines through focused research and development are essential for the world's future ability to treat and control malaria. Unfortunately, malaria is a disease of poverty, and despite a wealth of scientific knowledge there is insufficient market incentive to generate the competitive, business-driven industrial antimalarial drug research and development that is normally needed to deliver new products. Mechanisms of partnering with industry have been established to overcome this obstacle and to open up and build on scientific opportunities for improved chemotherapy in the future.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Future Med Chem
                Journal ID (iso-abbrev): Future Med Chem
                Journal ID (publisher-id): FMC
                Title: Future Medicinal Chemistry
                Publisher: Newlands Press Ltd (London, UK )
                ISSN (Print): 1756-8919
                ISSN (Electronic): 1756-8927
                Publication date (Electronic, pub): 05 December 2019
                Publication date (Print, pub): February 2020
                Publication date PMC-release: 05 December 2019
                Volume: 12
                Issue: 3
                Pages: 193-205
                Affiliations
                [1 ]Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India
                [2 ]Department of Medicine, University of California, San Francisco, CA 94143, USA
                [3 ]Department of Pharmaceutical Chemistry, University of KwaZulu-Natal, Durban 4000, South Africa
                [4 ]Department of Industrial Chemistry, Federal University of Oye-Ekiti, Nigeria
                [5 ]School of Chemistry & Physics, University of KwaZulu-Natal, Westville, Durban 4000, South Africa
                Author notes
                [* ]Author for correspondence: email:vipan_org@ 123456yahoo.com
                Author information
                https://orcid.org/0000-0003-2421-1382
                Article
                DOI: 10.4155/fmc-2019-0260
                PMC ID: 7099627
                PubMed ID: 31802710
                SO-VID: 42724a9b-35ef-460f-8d0e-4c61d1c8ab4b
                Copyright © © 2019 Newlands Press
                License:

                This work is licensed under the Creative Commons Attribution 4.0 License

                History
                Date received : 06 September 2019
                Date accepted : 14 November 2019
                Date: 05 December 2019
                Page count
                Pages: 13
                Categories
                Subject: Research Article

                Keywords: antiplasmodial,cycloalkyl-amine,cytotoxicity,density functional theory,heme-binding studies,isoindoline-1,3-dione-4-aminoquinoline,microwave
                Data availability:
                Keywords: antiplasmodial, cycloalkyl-amine, cytotoxicity, density functional theory, heme-binding studies, isoindoline-1,3-dione-4-aminoquinoline, microwave

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