Organic Reactivity and Medicinal Chemistry | CCMAR

Organic Reactivity and Medicinal Chemistry

Short Title 
OrgMedChem
Description 

Development of heterocyclic compounds applicable in medicine, environmental remediation or aquaculture. Investigation of structure, reactivity and activity of compounds obtained from synthesis or natural sources.

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The group applies the methods and tools of Physical Organic Chemistry and Medicinal Chemistry to investigate structure/reactivity/activity relationships of selected compounds from biologically relevant chemotypes: endoperoxydes, quinolones, tetrazoles and saccharins. We aim to contribute to the elucidation of interactions between compounds and their biological targets, thereby gathering instrumental information for rational drug design and optimization.

Topic 1. Development of anti-infective agents comprising quinolone- or peroxide-based heterocycles.

We investigate structural requirements of 4-oxoquinoline-3-esters for inhibition of the bc1 complex (respiratory chain) of Plasmodium falciparum (CQ-sensitive and multiresistant strains). Selected 2-substituted-4-oxoquinolines prepared exhibit potent activity against Mycobacterium tuberculosis.

Inspired in the antimalarial drug Artemisinin, a natural product, we develop synthetic endoperoxides with improved pharmacologic profile. We consider exploring peroxides inspired in Plakortin, a peroxide-based metabolite obtained from the marine sponge Plakortis halichondrioides.

We scrutinize the potencial of endoperoxides against other protozoans: Leishmania donovani, Perkinsus olseni, and Amyloodinium ocellatum the causative agents of Leishmaniases (in mamals), Perkinsosis (in bivalves) and Amyloodinium ocellatum (in fish), respectively.

Topic 2. Synthesis, reactivity and applications of chelants derived from tetrazole and saccharin.

We develop tetrazole-saccharyl conjugates as selective chelants and scrutinise their potential in catalysis, environmental remediation, medicine and in the design of supramolecular frameworks.

We demonstrated their utility as ligands for divalent cations. Selected copper complexes act as effective catalysts for oxidation of secondary alcohols and have shown potent cytotoxicity against adherent cancer cell lines.

 

We are organizing the 24TH IUPAC INTERNATIONAL CONFERENCE ON PHYSICAL ORGANIC CHEMISTRY (ICPOC 24) this year.

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ICPOC 24

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Publications
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Frija LMT, Kuznetsov ML, Rocha BGM, et al. Organocatalyzed oxidation of benzyl alcohols by a tetrazole-amino-saccharin: A combined experimental and theoretical (DFT) study. Molecular Catalysis. 2017;442:57 - 65. doi:10.1016/j.mcat.2017.09.003.
Mestre ALG, Inácio PMC, Elamine Y, et al. Extracellular Electrophysiological Measurements of Cooperative Signals in Astrocytes Populations. Frontiers in Neural Circuits. 2017;11. doi:10.3389/fncir.2017.00080.
Mestre ALG, Cerquido M, Inácio PMC, et al. Ultrasensitive gold micro-structured electrodes enabling the detection of extra-cellular long-lasting potentials in astrocytes populations. Scientific Reports. 2017;7(1). doi:10.1038/s41598-017-14697-y.
Cabral LIL, Henriques MSC, Paixão JA, Cristiano MLS. Synthesis and structure of 2-substituted pyrene-derived scaffolds. Tetrahedron Letters. 2017;58(48):4547 - 4550. doi:10.1016/j.tetlet.2017.10.058.
W. Hong D, Gibbons PD, Leung SC, et al. Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis. Journal of Medicinal Chemistry. 2017;60(9):3703 - 3726. doi:10.1021/acs.jmedchem.6b01718.
Horta P, Henriques MSC, Brás EM, et al. On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylateAbstract. Pure and Applied Chemistry. 2017;89(6). doi:10.1515/pac-2016-1119.
Cabral LIL, Brás E, Henriques M, et al. Synthesis, Structure and Cytotoxicity of a Novel Sulphanyl-Bridged Thiadiazolyl-Saccharinate Conjugate. The Relevance of S…N Interaction. Chemistry - A European Journal. 2017. doi:10.1002/chem.201705319.
Ismael A, Henriques MSC, Marques C, et al. Exploring saccharinate-tetrazoles as selective Cu(. RSC Adv. 2016;6(75):71628 - 71637. doi:10.1039/C6RA15051A.
Lobo L, de Sousa B, Cabral LIL, Cristiano MLS, Nogueira F. Highly active ozonides selected against drug resistant malaria. Memórias do Instituto Oswaldo Cruz. 2016;111(7):450 - 453. doi:10.1590/0074-02760160077.
Frija LMT, Alegria ECBA, Sutradhar M, et al. Copper(II) and cobalt(II) tetrazole-saccharinate complexes as effective catalysts for oxidation of secondary alcohols. Journal of Molecular Catalysis A: Chemical. 2016;425:283 - 290. doi:10.1016/j.molcata.2016.10.023.
Ismael A, Fausto R, Cristiano MLS. Photochemistry of 1- and 2-Methyl-5-aminotetrazoles: Structural Effects on Reaction Pathways. The Journal of Organic Chemistry. 2016;81(23):11656 - 11663. doi:10.1021/acs.joc.6b02023.
Ismael A, Borba A, Henriques MSC, Paixão JA, Fausto R, Cristiano MLS. Structure and photochemistry of a saccharyl thiotetrazole. J Org Chem. 2015;80(1):392-400. doi:10.1021/jo502419u.
Borba A, Cabral LIL, Fausto R, Cristiano MLS. Structure, vibrational spectroscopy, and photochemistry of 5-phenoxy-1-phenyltetrazole in argon and nitrogen cryomatrices. Canadian Journal of Chemistry. 2015;93(12):1335 - 1344. doi:10.1139/cjc-2015-0025.
Horta PC, Henriques MSC, Kuş N, et al. Synthesis, structural and conformational analysis, and IR spectra of ethyl 4-chloro-7-iodoquinoline-3-carboxylate. Tetrahedron. 2015;71(40):7583 - 7592. doi:10.1016/j.tet.2015.07.076.
Horta P, Kuş N, Henriques MSofia C, et al. Quinolone-Hydroxyquinoline Tautomerism in Quinolone 3-Esters. Preserving the 4-Oxoquinoline Structure To Retain Antimalarial Activity. J Org Chem. 2015;80(24):12244-57. doi:10.1021/acs.joc.5b02169.
Cortes S, Albuquerque A, Cabral LIL, Lopes L, Campino L, Cristiano MLS. In Vitro Susceptibility of Leishmania infantum to Artemisinin Derivatives and Selected Trioxolanes. Antimicrob Agents Chemother. 2015;59(8):5032-5. doi:10.1128/AAC.00298-15.
Ismael A, Gago DJP, Cabral LIL, Fausto R, Cristiano MLS. Investigations into the Mechanism of Solvolysis of 3-aryloxybenzisothiazoles. Croatica Chemica Acta. 2014;87(4):363 - 373. doi:10.5562/cca2478.
Frija LMT, Cristiano MLS, Gómez-Zavaglia A, Reva I, Fausto R. Genesis of rare molecules using light-induced reactions of matrix-isolated tetrazoles. Journal of Photochemistry and Photobiology C: Photochemistry Reviews. 2014;18:71 - 90. doi:10.1016/j.jphotochemrev.2013.09.001.
Ismael A, Serpa C, Cristiano MLS. Photochemistry of 1-allyl-4-aryltetrazolones in solution; structural effects on photoproduct selectivity. Photochem Photobiol Sci. 2013;12(2):272-83. doi:10.1039/c2pp25210d.
Duarte L, Reva I, Cristiano MLS, Fausto R. Photoisomerization of saccharin. J Org Chem. 2013;78(7):3271-5. doi:10.1021/jo400191p.
La Pensée L, Sabbani S, Sharma R, et al. Artemisinin-polypyrrole conjugates: synthesis, DNA binding studies and preliminary antiproliferative evaluation. ChemMedChem. 2013;8(5):709-18. doi:10.1002/cmdc.201200536.
Ismael A, Gómez-Zavaglia A, Borba A, Cristiano MLS, Fausto R. Amino→imino tautomerization upon in vacuo sublimation of 2-methyltetrazole-saccharinate as probed by matrix isolation infrared spectroscopy. J Phys Chem A. 2013;117(15):3190-7. doi:10.1021/jp401360c.
Cabral LIL, Maria TMR, Martelo L, Eusébio MES, Cristiano MLS, Fausto R. The thermal sigmatropic isomerization of pseudosaccharyl crotyl ether. Tetrahedron. 2013;69(2):810 - 815. doi:10.1016/j.tet.2012.10.100.
Araujo NCP, Afonso R, Bringela A, M. Cancela L, Cristiano MLS, Leite RB. Peroxides with antiplasmodial activity inhibit proliferation of Perkinsus olseni, the causative agent of Perkinsosis in bivalves. Parasitol Int. 2013;62(6):575-82. doi:10.1016/j.parint.2013.06.010.
Ismael A, Paixão JAntónio, Fausto R, Cristiano MLS. Molecular structure of nitrogen-linked methyltetrazole-saccharinates. Journal of Molecular Structure. 2012;1023:128 - 142. doi:10.1016/j.molstruc.2012.04.018.
Ismael A, Borba A, Duarte L, Giuliano BM, Gómez-Zavaglia A, Cristiano MLS. Structure and photochemistry of a novel tetrazole-saccharyl conjugate isolated in solid argon. Journal of Molecular Structure. 2012;1025:105 - 116. doi:10.1016/j.molstruc.2012.04.081.
Gómez-Zavaglia A, Ismael A, Cabral LIL, et al. Structural investigation of nitrogen-linked saccharinate–tetrazole. Journal of Molecular Structure. 2011;1003(1-3):103 - 110. doi:10.1016/j.molstruc.2011.07.044.
Frija LMT, Reva I, Ismael A, Coelho DV, Fausto R, Cristiano MLS. Sigmatropic rearrangements in 5-allyloxytetrazoles. Org Biomol Chem. 2011;9(17):6040-54. doi:10.1039/c1ob05460k.
Ismael A, Cristiano MLS, Fausto R, Gómez-Zavaglia A. Tautomer selective photochemistry in 1-(tetrazol-5-yl)ethanol. J Phys Chem A. 2010;114(50):13076-85. doi:10.1021/jp109215q.
Frija LMiguel Teo, Ismael A, Cristiano MLS. Photochemical transformations of tetrazole derivatives: applications in organic synthesis. Molecules. 2010;15(5):3757-74. doi:10.3390/molecules15053757.
Gibbons P, Verissimo E, Araujo NC, et al. Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entity. J Med Chem. 2010;53(22):8202-6. doi:10.1021/jm1009567.
Almeida R, Gómez-Zavaglia A, Kaczor A, Ismael A, Cristiano MLS, Fausto R. Matrix-isolation FTIR, theoretical structural analysis and reactivity of amino-saccharins: N-(1,1-dioxo-1,2-benzisothiazol-3-yl)-N-methyl amine and -N,N-dimethyl amine. Journal of Molecular Structure. 2009;938(1-3):198 - 206. doi:10.1016/j.molstruc.2009.09.027.
Gómez-Zavaglia A, Kaczor A, Coelho D, Cristiano MLS, Fausto R. Conformational and structural analysis of 2-allyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide as probed by matrix-isolation spectroscopy and quantum chemical calculations. Journal of Molecular Structure. 2009;919(1-3):271 - 276. doi:10.1016/j.molstruc.2008.09.013.
Araújo NCP, Barton V, Jones M, et al. Semi-synthetic and synthetic 1,2,4-trioxaquines and 1,2,4-trioxolaquines: synthesis, preliminary SAR and comparison with acridine endoperoxide conjugates. Bioorg Med Chem Lett. 2009;19(7):2038-43. doi:10.1016/j.bmcl.2009.02.013.
Frija LMT, Fausto R, Loureiro RMS, Cristiano MLS. Synthesis and structure of novel benzisothiazole-tetrazolyl derivatives for potential application as nitrogen ligands. Journal of Molecular Catalysis A: Chemical. 2009;305(1-2):142 - 146. doi:10.1016/j.molcata.2008.12.007.
Gómez-Zavaglia A, Kaczor A, Almeida R, et al. Thermally induced sigmatropic isomerization of pseudosaccharyl allylic ether. J Phys Chem A. 2009;113(15):3517-22. doi:10.1021/jp8112254.
Kaczor A, Almeida R, Gómez-Zavaglia A, Cristiano MLS, Fausto R. Molecular structure and infrared spectra of the monomeric 3-(methoxy)-1,2-benzisothiazole 1,1-dioxide (methyl pseudosaccharyl ether). Journal of Molecular Structure. 2008;876(1-3):77 - 85. doi:10.1016/j.molstruc.2007.06.004.
Gómez-Zavaglia A, Kaczor A, Almeida R, Cristiano MLS, Fausto R. Conformational Space of the P seudo saccharin Allyl Ether 3-(Allyloxy)-1,2-benzisothiazole 1,1-Dioxide in Gas Phase and in Rare Gas Matrices. The Journal of Physical Chemistry A. 2008;112(8):1762 - 1772. doi:10.1021/jp0770918.
Frija LMT, Khmelinskii IV, Serpa C, Reva ID, Fausto R, Cristiano MLS. Photochemistry of 5-allyloxy-tetrazoles: steady-state and laser flash photolysis study. Organic & Biomolecular Chemistry. 2008;6(6):1046. doi:10.1039/b718104c.
Cristiano MLS, Ruasse M-F. Editorial. Journal of Physical Organic Chemistry. 2008;21(7-8):523 - 523. doi:10.1002/poc.1411.
Gómez-Zavaglia A, Kaczor A, Almeida R, Cristiano MLS, Fausto R. Conformational space of the Pseudosaccharin allyl ether 3-(allyloxy)-1,2-benzisothiazole 1,1-dioxide in gas phase and in rare gas matrices. J Phys Chem A. 2008;112(8):1762-72. doi:10.1021/jp0770918.
Verissimo E, Berry N, Gibbons P, et al. Design and synthesis of novel 2-pyridone peptidomimetic falcipain 2/3 inhibitors. Bioorganic & Medicinal Chemistry Letters. 2008;18(14):4210 - 4214. doi:10.1016/j.bmcl.2008.05.068.
Frija LMT, Khmelinskii IV, Serpa C, Reva ID, Fausto R, Cristiano MLS. Photochemistry of 5-allyloxy-tetrazoles: steady-state and laser flash photolysis study. Org Biomol Chem. 2008;6(6):1046-55. doi:10.1039/b718104c.
Kaczor A, Proniewicz LM, Almeida R, et al. The Chapman-type rearrangement in pseudosaccharins: The case of 3-(methoxy)-1,2-benzisothiazole 1,1-dioxide. Journal of Molecular Structure. 2008;892(1-3):343 - 352. doi:10.1016/j.molstruc.2008.05.054.
Verissimo E, Berry N, Gibbons P, et al. Design and synthesis of novel 2-pyridone peptidomimetic falcipain 2/3 inhibitors. Bioorg Med Chem Lett. 2008;18(14):4210-4. doi:10.1016/j.bmcl.2008.05.068.
Frija LMT, Reva ID, Gómez-Zavaglia A, Cristiano MLS, Fausto R. Photochemistry and vibrational spectra of matrix-isolated 5-ethoxy-1-phenyl-1H-tetrazole. J Phys Chem A. 2007;111(15):2879-88. doi:10.1021/jp068556h.
Frija LMT, Reva ID, Gómez-Zavaglia A, Cristiano MLS, Fausto R. UV-induced photochemistry of matrix-isolated 1-phenyl-4-allyl-tetrazolone. Photochem Photobiol Sci. 2007;6(11):1170-6. doi:10.1039/b703961a.
Gómez-Zavaglia A, Reva ID, Frija L, Cristiano MLS, Fausto R. Molecular structure, vibrational spectra and photochemistry of 5-mercapto-1-methyltetrazole. Journal of Molecular Structure. 2006;786(2-3):182 - 192. doi:10.1016/j.molstruc.2005.08.019.
Gómez-Zavaglia A, Reva ID, Frija L, Cristiano MLS, Fausto R. Photochemistry of 1-phenyl-tetrazolone isolated in solid argon. Journal of Photochemistry and Photobiology A: Chemistry. 2006;179(3):243 - 255. doi:10.1016/j.jphotochem.2005.08.021.
Breda S, Reva I, Lapinski L, Cristiano MLS, Frija L, Fausto R. Photochemical Ring-Opening and Intramolecular Hydrogen Shift Reactions in Sulfur Analogues of α-Pyrone. The Journal of Physical Chemistry A. 2006;110(20):6415 - 6425. doi:10.1021/jp061139k.
Frija LMT, Khmelinskii IV, Cristiano MLS. Mechanistic investigations into the photochemistry of 4-allyl-tetrazolones in solution: a new approach to the synthesis of 3,4-dihydro-pyrimidinones. J Org Chem. 2006;71(9):3583-91. doi:10.1021/jo060164j.
Gómez-Zavaglia A, Reva ID, Frija L, Cristiano MLS, Fausto R. Molecular Structure, Vibrational Spectra and Photochemistry of 2-Methyl-2 H -Tetrazol-5-Amine in Solid Argon. The Journal of Physical Chemistry A. 2005;109(35):7967 - 7976. doi:10.1021/jp0517706.
Frija LMT, Cristiano MLS, Guimarães EMO, Martins NC, Loureiro RMS, Bickley JF. Palladium-catalysed reduction of heteroaromatic naphthyl ethers: Structural effects on reactivity. Journal of Molecular Catalysis A: Chemical. 2005;242(1-2):241 - 250. doi:10.1016/j.molcata.2005.08.022.
Araújo NCP, Brigas AF, Cristiano MLS, Frija LMT, Guimarães EMO, Loureiro RMS. Heteroaromatic benzyl ethers as intermediates for palladium-catalysed transfer hydrogenolysis of benzyl alcohols. Journal of Molecular Catalysis A: Chemical. 2004;215(1-2):113 - 120. doi:10.1016/j.molcata.2003.12.033.
Cristiano MLS, Gago DJP, Gonsalves AM d'ARo, Johnstone RAW, McCarron M, Varejão JMTB. Investigations into the mechanism of action of nitrobenzene as a mild dehydrogenating agent under acid-catalysed conditions. Organic & Biomolecular Chemistry. 2003;1(3):565 - 574. doi:10.1039/b210887a.
Araújo NCP, Barroca PMM, Bickley JF, et al. Structural effects on sigmatropic shifts in heteroaromatic allyl ethersElectronic supplementary information (ESI) available: selected crystal data for compound 7. See http://www.rsc.org/suppdata/p1/b1/b102674g/. Journal of the Chemical Society, Perkin Transactions 1. 2002;(9):1213 - 1219. doi:10.1039/b102674g.
Bugalho SCS, Serra AC, Lapinski L, Cristiano MLS, Fausto R. Low temperature matrix-isolation and solid state vibrational spectra of 5-chlorotetrazoleElectronic supplementary information (ESI) available: Calculated molecular geometries, rotational constants, energies and dipole moments. . Physical Chemistry Chemical Physics. 2002;4(10):1725 - 1731. doi:10.1039/b111329c.
Bugalho SCS, Lapinski L, Cristiano MLS, Frija LMT, Fausto R. Vibrational spectra and structure of 1-phenyltetrazole and 5-chloro-1-phenyltetrazole. Vibrational Spectroscopy. 2002;30(2):213 - 225. doi:10.1016/S0924-2031(02)00028-0.
Bugalho SCS, Maçôas EMS, Cristiano MLS, Fausto R. Low temperature matrix-isolation and solid state vibrational spectra of tetrazole. Physical Chemistry Chemical Physics. 2001;3(17):3541 - 3547. doi:10.1039/b103344c.
Cristiano MLS, Brigas AF, Johnstone RAW, Loureiro RMS, Pena PCA. Thermal Rearrangement of 3-Allyloxy-1,2-benzisothiazole 1,1-Dioxides: an Unusual Inversion of Products of Sigmatropic [3,3]-Shift to Give the [1,3]-Isomers. Journal of Chemical Research. 1999;(12):704 - 705. doi:10.1039/a906750g.
Lurdes M, Cristiano MLS, Johnstone RAW. A kinetic investigation of the thermal rearrangement of allyloxytetrazoles to N-allyltetrazolones. Journal of the Chemical Society, Perkin Transactions 2. 1997;(3):489 - 494. doi:10.1039/a606376d.
Cristiano MLS, Johnstone RAW. Intramolecularity of the Thermal Rearrangement of Allyloxytetrazoles to N-Allyltetrazolones†. Journal of Chemical Research. 1997;(5):164 - 165. doi:10.1039/a608333a.
Barkley JV, Cristiano MLS, Johnstone RAW, Loureiro RMS. 3-( E )-But-2-enoxy-1,2-benzisothiazole 1,1-Dioxide: Unusual C—O—C Ether Bond Lengths and Reactivity. Acta Crystallographica Section C Crystal Structure Communications. 1997;53(3):383 - 386. doi:10.1107/S0108270196014151/bm1104sup2.hkl.
Cristiano MLS, Johnstone RAW, Price PJ. Metal-assisted reactions. Part 25. Heterogeneous and homogeneous catalytic transfer hydrogenolysis of allyloxytetrazoles to yield alkenes or alkanes. Journal of the Chemical Society, Perkin Transactions 1. 1996;(12):1453. doi:10.1039/p19960001453.
Cristiano MLS, Johnstone RAW, Pratt MJ. 3-Hydroxy-2,6-dinitroacetophenone: an Unusual Substitution Pattern Resulting from Nitration of 3-Hydroxyacetophenone. Acta Crystallographica Section C Crystal Structure Communications. 1995;51(12):2581 - 2583. doi:10.1107/S0108270195007451.
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