The resistance among microbes has brought an urgent need for new drugs. Thus, we synthesized a series of Schiff bases derived from the sulfa drug sulfadiazine and various salicylaldehydes. The resulting 4-[(2-hydroxybenzylidene)amino]-N-(pyrimidin-2-yl)benzene-sulfonamides were characterized and evaluated against Gram-positive and Gram-negative bacteria, yeasts, moulds, Mycobacterium tuberculosis, nontuberculous mycobacteria (M. kansasii, M. avium) and their cytotoxicity was determined. Among bacteria, the genus Staphylococcus, including methicillin-resistant S. aureus, showed the highest susceptibility, with minimum inhibitory concentration values from 7.81 µM. The growth of Candida sp. and Trichophyton interdigitale was inhibited at concentrations starting from 1.95 µM. 4-[(2,5-Dihydroxybenzylidene)amino]-N-(pyrimidin-2-yl)-benzenesulfonamide was identified as the most selective Schiff base for these strains with no apparent cytotoxicity and a selectivity index higher than 16. With respect to M. tuberculosis and M. kansasii that were inhibited within the range of 8 to 250 µM, unsubstituted 4-[(2-hydroxy-benzylidene)amino]-N-(pyrimidin-2-yl)benzenesulfonamide meets the selectivity requirement. In general, dihalogenation of the salicylic moiety improved the antibacterial and antifungal activity but also increased the cytotoxicity, especially with an increasing atomic mass. Some derivatives offer more advantageous properties than the parent sulfadiazine, thus constituting promising hits for further antimicrobial drug development.

Department of Biological and Medical Sciences Faculty of Pharmacy Charles University Akademika Heyrovského 1203 500 05 Hradec Králové Czech Republic

Department of Chemistry Faculty of Science J E Purkinje University České mládeže 8 400 96 Ústí nad Labem Czech Republic

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy in Hradec Králové Charles University Akademika Heyrovského 1203 500 05 Hradec Králové Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy Charles University Akademika Heyrovského 1203 500 05 Hradec Králové Czech Republic

Laboratory for Mycobacterial Diagnostics and Tuberculosis Regional Institute of Public Health in Ostrava Partyzánské námĕstí 7 702 00 Ostrava Czech Republic

See more in PubMed

Da Silva C.M., da Silva D.L., Modolo L.V., Alves R.B., de Resende M.A., Martins C.V.B., de Fátima A. Schiff bases: A short review of their antimicrobial activities. J. Adv. Res. 2011;2:1–8. doi: 10.1016/j.jare.2010.05.004. DOI

Qin W., Long S., Panunzio M., Biondi S. Schiff Bases: A short survey on an evergreen chemistry tool. Molecules. 2013;18:12264–12289. doi: 10.3390/molecules181012264. PubMed DOI PMC

Kajal A., Bala S., Kamboj S., Sharma N., Saini V. Schiff bases: A versatile pharmacophore. J. Catal. 2013;2013 doi: 10.1155/2013/893512. DOI

Krátký M., Vinšová J., Volková M., Buchta V., Trejtnar F., Stolaříková J. Antimicrobial activity of sulfonamides containing 5-chloro-2-hydroxybenzaldehyde and 5-chloro-2-hydroxybenzoic acid scaffold. Eur. J. Med. Chem. 2012;50:433–440. doi: 10.1016/j.ejmech.2012.01.060. PubMed DOI

Yıldız M., Tan E., Demir N., Yıldırım N., Ünver H., Kiraz A., Mestav B. Synthesis and spectral, antimicrobial, anion sensing, and DNA binding properties of Schiff base podands and their metal complexes. Russ. J. Gen. Chem. 2015;85:2149–2162. doi: 10.1134/S1070363215090200. DOI

Shi L., Ge M.M., Tan S.H., Li H.Q., Song Y.C., Zhu H.L., Tan R.X. Synthesis and antimicrobial activities of Schiff bases derived from 5-chloro-salicylaldehyde. Eur. J. Med. Chem. 2007;42:558–564. doi: 10.1016/j.ejmech.2006.11.010. PubMed DOI

Govindaraj V., Ramanathan S. Synthesis, spectral characterisation, electrochemical, and fluorescence studies of biologically active novel Schiff base complexes derived from E-4-(2-hydroxy-3-methoxybenzlideneamino)-N-(pyrimidin-2-yl)benzenesulfonamide. Turk. J. Chem. 2014;38:521–530. doi: 10.3906/kim-1301-83. DOI

Mondal S., Mandal S.M., Mondal T.K., Sinha C. Spectroscopic characterization, antimicrobial activity, DFT computation and docking studies of sulfonamide Schiff bases. J. Mol. Struct. 2017;1127:557–567. doi: 10.1016/j.molstruc.2016.08.011. DOI

Chohan Z.H., Youssoufi M.H., Jarrahpour A., Hadda T.B. Identification of antibacterial and antifungal pharmacophore sites for potent bacteria and fungi inhibition: Indolenyl sulfonamide derivatives. Eur. J. Med. Chem. 2010;45:1189–1199. doi: 10.1016/j.ejmech.2009.11.029. PubMed DOI

Ameen S.M., Drancourt M. In Vitro susceptibility of Mycobacterium tuberculosis to trimethoprim and sulfonamides in France. Antimicrob. Agents Chemother. 2013;57:6370–6371. doi: 10.1128/AAC.01683-13. PubMed DOI PMC

Ameen S.M., Drancourt M. In vitro susceptibility of Mycobacterium avium complex mycobacteria to trimethoprim and sulfonamides. Int. J. Antimicrob. Agents. 2013;42:281–288. doi: 10.1016/j.ijantimicag.2013.05.006. PubMed DOI

El-Baradie K.Y. Preparation and characterization of sulfadiazine Schiff base complexes of Co(II), Ni(II), Cu(II), and Mn(II) Monatshefte Chem. 2005;136:1139–1155. doi: 10.1007/s00706-004-0257-8. DOI

Chohan Z.H., Shad H.A., Youssoufi M.H., Hadda T.B. Some new biologically active metal-based sulphonamide. Eur. J. Med. Chem. 2010;45:2893–2901. doi: 10.1016/j.ejmech.2010.03.014. PubMed DOI

Abdel-Aal W.S., Hassan H.Y., Aboul-Fadl T., Youssef A.F. Pharmacophoric model building for antitubercular activity of the individual Schiff bases of small combinatorial library. Eur. J. Med. Chem. 2010;45:1098–1106. doi: 10.1016/j.ejmech.2009.12.005. PubMed DOI

Zorzi R.R., Jorge S.D., Palace-Berl F., Pasqualoto K.F.M., de Sa Bortolozzo L., de Castro Siqueira A.M., Tavares L.C. Exploring 5-nitrofuran derivatives against nosocomial pathogens: Synthesis, antimicrobial activity and chemometric analysis. Bioorg. Med. Chem. 2014;22:2844–2854. doi: 10.1016/j.bmc.2014.03.044. PubMed DOI

Krátký M., Vinšová J., Novotná E., Mandíková J., Trejtnar F., Stolaříková J. Antibacterial activity of salicylanilide 4-(Trifluoromethyl)benzoates. Molecules. 2013;18:3674–3688. doi: 10.3390/molecules18043674. PubMed DOI PMC

Krátký M., Vinšová J. Antifungal activity of salicylanilides and their esters with 4-(Trifluoromethyl)benzoic acid. Molecules. 2012;17:9426–9442. doi: 10.3390/molecules17089426. PubMed DOI PMC

Sriram D., Yogeeswari P., Dhakla P., Senthilkumar P., Banerjee D., Manjashetty T.H. 5-Nitrofuran-2-yl derivatives: Synthesis and inhibitory activities against growing and dormant mycobacterium species. Bioorg. Med. Chem. Lett. 2009;19:1152–1154. doi: 10.1016/j.bmcl.2008.12.088. PubMed DOI

Castle R.N., Witt N.F., Poe C.F. The optical crystallographic properties of some sulfonamides and their derivatives. J. Am. Chem. Soc. 1949;71:228–231. doi: 10.1021/ja01169a059. PubMed DOI

Tsukamoto T., Yuhi K. Studies on halogenosalicylaldehyde. I halogenosalicylaldehyde as reagent for primary amines. Yakugaku Zasshi. 1958;78:706–709. doi: 10.1248/yakushi1947.78.7_706. DOI

Krátký M., Vinšová J., Novotná E., Wsól V., Ulmann V., Stolaříková J., Fernandes S., Bhat S., Liu J.O. Salicylanilide derivatives block Mycobacterium tuberculosis through inhibition of isocitrate lyase and methionine aminopeptidase. Tuberculosis (Edinb.) 2012;92:434–439. doi: 10.1016/j.tube.2012.06.001. PubMed DOI

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