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      Cinnamic Acid Conjugates in the Rescuing and Repurposing of Classical Antimalarial Drugs

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          Abstract

          Cinnamic acids are compounds of natural origin that can be found in many different parts of a wide panoply of plants, where they play the most diverse biological roles, often in a conjugated form. For a long time, this has been driving Medicinal Chemists towards the investigation of the therapeutic potential of natural, semi-synthetic, or fully synthetic cinnamic acid conjugates. These efforts have been steadily disclosing promising drug leads, but a wide chemical space remains that deserves to be further explored. Amongst different reported approaches, the combination or conjugation of cinnamic acids with known drugs has been addressed in an attempt to produce either synergistic or multi-target action. In this connection, the present review will focus on efforts of the past decade regarding conjugation with cinnamic acids as a tool for the rescuing or the repurposing of classical antimalarial drugs, and also on future perspectives in this particular field of research.

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          Biological Activity of Ionic Liquids and Their Application in Pharmaceutics and Medicine

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            Antibacterial Properties of Polyphenols: Characterization and QSAR (Quantitative Structure–Activity Relationship) Models

            Besides their established antioxidant activity, many phenolic compounds may exhibit significant antibacterial activity. Here, the effect of a large dataset of 35 polyphenols on the growth of 6 foodborne pathogenic or food-spoiling bacterial strains, three Gram-positive ones (Staphylococcus aureus, Bacillus subtilis, and Listeria monocytogenes) and three Gram-negative ones (Escherichia coli, Pseudomonas aeruginosa, and Salmonella Enteritidis), have been characterized. As expected, the effects of phenolic compounds were highly heterogeneous ranging from bacterial growth stimulation to antibacterial activity and depended on bacterial strains. The effect on bacterial growth of each of the polyphenols was expressed as relative Bacterial Load Difference (BLD) between a culture with and without (control) polyphenols at a 1 g L−1 concentration after 24 h incubation at 37°C. Reliable Quantitative Structure-Activity Relationship (QSAR) models were developed (regardless of polyphenol class or the mechanism of action involved) to predict BLD for E. coli, S. Enteritidis, S. aureus, and B. subtilis, unlike for L. monocytogenes and P. aeruginosa. L. monocytogenes was generally sensitive to polyphenols whereas P. aeruginosa was not. No satisfactory models predicting the BLD of P. aeruginosa and L. monocytogenes were obtained due to their specific and quite constant behavior toward polyphenols. The main descriptors involved in reliable QSAR models were the lipophilicity and the electronic and charge properties of the polyphenols. The models developed for the two Gram-negative bacteria (E. coli, S. Enteritidis) were comparable suggesting similar mechanisms of toxic action. This was not clearly observed for the two Gram-positive bacteria (S. aureus and B. subtilis). Interestingly, a preliminary evaluation by Microbial Adhesion To Solvents (MATS) measurements of surface properties of the two Gram-negative bacteria for which QSAR models were based on similar physico-chemical descriptors, revealed that MATS results were also quite similar. Moreover, the MATS results of the two Gram-positive bacterial strains S. aureus and B. subtilis for which QSARs were not based on similar physico-chemical descriptors also strongly differed. These observations suggest that the antibacterial activity of most of polyphenols likely depends on interactions between polyphenols and bacterial cells surface, although the surface properties of the bacterial strains should be further investigated with other techniques than MATS.
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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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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                24 December 2019
                January 2020
                : 25
                : 1
                : 66
                Affiliations
                [1 ]LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, P-4169-007 Porto, Portugal; up201303026@ 123456gmail.com (A.T.S.); luisa.aguiarts@ 123456gmail.com (L.A.); ricardoferraz@ 123456eu.ipp.pt (R.F.); catia.teixeira@ 123456fc.up.pt (C.T.)
                [2 ]i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, P-4200-135 Porto, Portugal; clara.bento@ 123456i3s.up.pt (C.M.B.); tania.silva@ 123456ibmc.up.pt (T.S.); sgomes@ 123456ibmc.up.pt (M.S.G.)
                [3 ]IBMC—Instituto de Biologia Molecular e Celular, Universidade do Porto, P-4200-135 Porto, Portugal
                [4 ]Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, P-1649-028 Lisboa, Portugal; ana.c.d.pena@ 123456gmail.com (A.C.P.); lmf@ 123456medicina.ulisboa.pt (L.M.F.)
                [5 ]Ciências Químicas e das Biomoléculas, Escola Superior de Saúde—Instituto Politécnico do Porto, Rua Dr. António Bernardino de Almeida 400, P-4200-072 Porto, Portugal; cps@ 123456estsp.ipp.pt
                [6 ]ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, P-4050-313 Porto, Portugal
                Author notes
                [* ]Correspondence: pgomes@ 123456fc.up.pt
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-9019-7334
                https://orcid.org/0000-0002-6087-1487
                https://orcid.org/0000-0002-1761-117X
                https://orcid.org/0000-0001-7657-2118
                https://orcid.org/0000-0002-6018-4724
                Article
                molecules-25-00066
                10.3390/molecules25010066
                6982862
                31878190
                2ccc2f47-35b2-47c9-8d2d-6de37d1c362a
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 November 2019
                : 20 December 2019
                Categories
                Review

                amide,aminoquinoline,antimalarial,antioxidant,antiparasitic,antiproliferative,artemisinin,chloroquine,cinnamic,ionic liquid,primaquine,rescuing,repurposing

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