SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF DIHYDROQUINAZOLINES

JIMENA E. DÍAZ; LILIANA FERNÁNDEZ CANIGIA; PABLO STRIEBEK; LILIANA R. ORELLI

La Plata

Workshop; INTERNATIONAL WORKSHOP ON DRUG DESIGN AND NEGLECTED TROPICAL DISEASES; 2016

United Nations University y Universidad de La Plata

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF DIHYDROQUINAZOLINESJimena E. Díaz,1,2 Liliana Fernandez Canigia,2 Pablo Striebek,2 Liliana R. Orelli11 Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica.Universidad de Buenos Aires, CONICET, Junín 956, Buenos Aires, Argentina.2 Laboratorio Domecq & Lafage. Hospital Alemán. Av. Pueyrredón 1640, Buenos Aires,ArgentinaE-mail: jediaz@ffyb.uba.arPurposeDihydroquinazolines are heterocyclic cores of wide pharmacological interest. Some derivatives containing this moiety have shown antiplatelet activity.1 Recently, their activity as Trypanothione Reductase inhibitors has been studied.2 The reported synthetic pathways for the dihydroquinazoline nucleus generally involve drastic reaction conditions, require selective N-monoprotection steps and/or lead to poor yields.3 In this context, we present an efficient method for the synthesis of novel 3,4- dihydroquinazolines 1 and 1,4-dihydroquinazolines 2 with different substitution patterns (Figure 1). We also present the evaluation of the antimicrobial activity against bacteria and fungi of some selected derivatives.MethodologyThe synthesis of compounds 1 and 2 was achieved following the pathway depicted in Scheme 1.For the evaluation of the antimicrobial activity we first performed the agar diffusion test employing a few examples of gram positive and gram negative bacteria and some species of fungi. On the basis of these results, we measured the Minimum Inhibitory Concentration (MIC) of some selected compounds against a larger number of species.ResultsDihydroquinazolines 1 and 2 where prepared with good yields. The cyclization of compounds 3 and 4 was achieved with a chloroform solution of ethyl polyphosphate (PPE) under microwave irradiation in a closed vessel reactor. The results are shown in Tables 1-4.The MICs of dihydroquinazolines 1c,d and 2d,e were measured. The compounds showed very moderate activity against gram positive strains of bacteria and two species of yeast. The results are shown in Table 5.ConclusionAn efficient route for the synthesis of 3,4 and 1,4-dihydroquinazolines was developed. Some compounds showed very moderate antibacterial and antifungal activity. Considering the structural analogy between dihydroquinazolines and quinolones, it could be hypothesize that these compounds inhibit DNA gyrase and topoisomerase IV from bacteria, interacting specifically with the GyrA and ParC subunits respectively where the binding sites of quinolones are located.References1. Ishikawa, F.; Watanabe, Y.; Saegusa, J. Chem. Pharm. Bull. 28, 1357 (1980)2. Patterson, S.; Alphey, M. S.; Jones, D. C.; Shanks, E. J.; Street, I. P.; Freaarson, J. A.; Wyatt, P. G.; Gilbert, I. H.; Fairlamb, A. H. J. Med. Chem. 54, 6514 (2011)3. For selected examples, see: (a) Los, R.; Wesolowska-Trojanowska, M.; Malm, A.; Karpinska, M. M.; Matysiak, J.; Niewiadomy, A.; Glaszcz, U. Heteroatom Chem. 23, 265 (2012) (b) Charton, J.; Girault-Mizzi, S.; Debreu-Fontaine, M.; Foufelle, F.; Hainault, I.; Bizot-Espiard, J.; Caignard, D.; Sergheraert, C. Bioorg. Med. Chem. 14, 4490 (2006) (c) Dietrich, J.; Kaiser, C.; Meurice, N.; Hulme, C. Tetrahedron Lett. 51, 3951 (2010) (d) Rohlmann, R.; Stopka, T.; Richter, H.; García Mancheño, O. J. Org. Chem. 78, 6050 (2013)