INTRODUCTION: Quinolines are an important class of heterocycles known in the literature for presenting different types of biological and pharmacological activities. Thus, in addition to being present in several natural products, several synthesis protocols for this ring have already been established with the aim of obtaining new medicines. Quinolines containing a carboxylic acid group have already been reported to present different types of biological activities.1 Furthermore, quinolines containing the styryl group are already important medicines used as bactericides, including aminoquinol, trichomonicide and quinifuril.2 Among a variety of synthetic approaches to obtain quinolinic acids, we highlight the Pfitzinger reaction, where isatin reacts with an ?-methylene carbonyl compound such as a ketone in the presence of a strong base.3 To obtain a quinoline containing the styryl group, the ketone used must be ?,?-unsaturated, which can be synthesized through a cross-aldol reaction between acetone and an aromatic aldehyde. Another possibility is to react 2-methyl-4-carboxylic acid (quinaldine), obtained by the Pfitzinger reaction between isatin and acetone, with an aromatic aldehyde through the Knoevenagel reaction.4 AIMS: The synthesis of 2-styryl-4-carboxylic acids using different methods, complete characterization of obtained compounds and evaluation of their respective bactericidal and fungicidal activities. METHODS: (E)-2-(4-hydroxy-3-methoxystyryl)quinoline-4-carboxylic acid (1) was obtained through the Pfitzinger reaction between isatin and (E)-4-(4-hydroxy-3-methoxyphenyl )but-3-en-2-one in aqueous solution of KOH and subsequently acidification with HCl(aq). Compounds 2 to 5 were obtained via the Knoevenagel reaction between quinaldine and aldehydes (vanillin, salicylaldehyde, 3,4-dimethoxy-benzaldehyde and 4-nitrobenzaldehyde) in acetic anhydride. The chemical structures of all final compounds were fully characterized by IR, 1H and 13C NMR. The targets analyzed were bacteria S. aureus ATCC-13150, S. epidermidis ATCC-12228 and P. aeruginosa ATCC-25853, and fungi C. albicans ATCC-76485, C. albicans LM-92, C. tropicalis ATCC-750, C. tropicalis LM-77, A. flavus ATCC-4603, A. flavus LM-248 and P. citrinum INCQS-4001. RESULTS AND DISCUSSION: The synthesis using the Pfitzinger protocol provided the pure product with a 27% yield in 9h, while Knoevenagel reactions gave yields of 43-93% after 3-5 h, thus being the best synthetic route adopted. The use of acetic anhydride favored the acetylation of the free OH group in compounds 2 and 3. The O-acetylation of phenols in pure acetic anhydride with no acid or base catalysts is not uncommon, however to the best of our knowledge, unknown in the literature for this particular reaction. All analyzed compounds showed biological activity on the growth of bacterial and fungal species, where the MIC was established between 128 and 512 ?g/mL, and the MBC and CFM between 256 and 1024 ?g/mL. Unicellular structures such as bacteria and yeast showed greater sensitivity to molecules than multicellular structures such as filamentous fungi. This is the case of molecules 2 and 3, where the MIC was 128 ?g/mL, while the MIC for filamentous fungi was 512 ?g/mL, that is, the presence of the acetyl group increased the activity against unicellular structures. The molecules produced 100% (7/7) inhibition of the growth of bacteria and yeast; Molecules 1, 4 and 5 produced inhibition on the growth of microorganisms where the MIC was between 256 and 512 ?g/mL and respective MBC/CFM was between 512 and 1024 ?g/mL. CONCLUSION: Five molecules derived from 2-styrylquinoline-4-carboxylic acids were synthesized and characterized. Although the synthetic method via the Pfitzinger reaction was satisfactory, the Knoevenagel reaction was more efficient. Depending on the MIC/CBM and CFM ratio, some molecules have bactericidal and fungicidal effects, others have bacteriostatic and fungistatic effects. ACKNOWLEDGEMENT: CNPq, INCT-Cimol, UFPB.
REFERENCES
1 B. S. Matada, R. Pattanashettar and N. G. Yernale, Bioorganic Med. Chem., 2021, 32, 115973.
2 M. Dhanawat, D. K. Mehta and R. Das, Mini-Reviews Med. Chem., 2021, 21, 1849–1864.
3 A. Luczywo, I. P. Sauter, T. C. da Silva Ferreira, M. Cortez, G. P. Romanelli, G. Sathicq and S. E. Asís, J. Heterocycl. Chem., 2021, 58, 822–832.
4 A. N. Dubrovin, A. I. Mikhalev, S. V. Ukhov, A. G. Goldshtein, V. V. Novikova, T. F. Odegova and R. R. Makhmudov, Pharm. Chem. J., 2015, 49, 309–312.
Comissão Organizadora
Francisco Mendonça Junior
Pascal Marchand
Teresinha Gonçalves da Silva
Isabelle Orliac-Garnier
Gerd Bruno da Rocha
Comissão Científica
Ricardo Olimpio de Moura
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