Synthesis of novel sulphamethoxazole derivatives and exploration of their anticancer and antimicrobial properties.

A series of new derivatives based on sulfamethoxazole were designed and synthesized in this study. The structures of the new compounds were confirmed based on a comprehensive characterization of spectral data by applied IR and 1H as well as 13C NMR spectroscopy. The prepared compounds were tested for their anticancer and antimicrobial properties. Hydrazone 16b demonstrated convincing anticancer effect against all tested cell cultures such as human prostate carcinoma PPC-1 and human kidney carcinoma CaKi-1 cell lines, and human fibroblasts HF, n = 3. The most promising compound 16b showed higher activity against CaKi-1 cell line than the anticancer drugs axitinib and pazopanib used to treat renal cancer. Also, it was more active in the PPC-1 cell line compared to the approved PARP inhibitor Olaparib. Hydrazone 16b was also found to possess good antimicrobial properties against gram-positive bacteria strains of Staphylococcus aureus, Staphylococcus epidermidis, as well as Bacillus cereus.

Pyrrolidinone-bearing methylated and halogenated benzenesulfonamides as inhibitors of carbonic anhydrases.

Two series of benzenesulfonamides bearing methyl groups at ortho/ortho or meta/ortho positions and a pyrrolidinone moiety at para position were synthesized and tested as inhibitors of the twelve catalytically active human carbonic anhydrase (CA) isoforms. Observed binding affinities were determined by fluorescent thermal shift assay and intrinsic binding affinities representing the binding of benzenesulfonamide anion to the Zn(II)-bound water form of CA were calculated. Introduction of dimethyl groups into benzenesulfonamide ring decreased the binding affinity to almost all CA isoforms, but gained in selectivity towards one CA isoform. A chloro group at the meta position of 2,6-dimethylbenzenesulfonamide derivatives did not influence the binding to CA I, but it increased the affinity to all other CAs, especially, CA VII and CA XIII (up to 500 fold). The compounds may be used for further development of CA inhibitors with higher selectivity to particular CA isoforms.

N-Sulfamoylphenyl- and N-sulfamoylphenyl-N-thiazolyl-ß-alanines and their derivatives as inhibitors of human carbonic anhydrases.

A series of N-substituted and N,N-disubstituted ß-amino acids and their derivatives bearing benzenesulfonamide moiety were designed and synthesized in search of compounds that would be high-affinity and selective inhibitors of human carbonic anhydrases (CA). There are 12 catalytically active human CA isoforms, the cytosolic CA I, CA II, CA III, CA VII, and CA XIII, secreted CA VI, the mitochondrial CA VA and CA VB, membrane-associated CA IV, and transmembrane CA IX, CA XII, and CA XIV. The di-bromo meta-substituted compounds exhibited low nanomolar dissociation constants and over 10-fold selectivity for mitochondrial isozyme CA VB, implicated in diseases of the central nervous system and obesity. These compounds can be used for further development as inhibitors of significant binding affinity and selectivity towards CA VB isozyme.