Synthesis and in silico studies of triazene-substituted sulfamerazine derivatives as acetylcholinesterase and carbonic anhydrases inhibitors.

A novel series of sulfonamides, 4-(3-phenyltriaz-1-en-1-yl)-N-(4-methyl-2-pyrimidinyl)benzenesulfonamides (1-9), was designed and synthesized by the diazo reaction between sulfamerazine and substituted aromatic amines for the first time. Their chemical structures were characterized by 1 H nuclear magnetic resonance (NMR), 13 C NMR, and high-resolution mass spectra. The newly synthesized compounds were evaluated in terms of acetylcholineasterase (AChE) and human carbonic anhydrases (hCA) I and II isoenzymes inhibitory activities. According to the AChE inhibition results, the Ki values of the compounds 1-9 were in the range of 19.9 ± 1.5 to 96.5 ± 20.7 nM against AChE. Tacrine was used as the reference drug and its Ki value was 49.2 ± 2.7 nM against AChE. The Ki values of the compounds 1-9 were in the range of 10.2 ± 2.6 to 101.4 ± 27.8 nM against hCA I, whereas they were 18.3 ± 4.4 to 48.1 ± 4.5 nM against hCA II. Acetazolamide was used as a reference drug and its Ki values were 72.2 ± 5.4 and 52.2 ± 5.7 nM against hCA I and hCA II, respectively. The most active compounds, 1 (nonsubstituted) against AChE, 5 (4-ethoxy-substituted) against hCA I, and 8 (4-bromo-substituted) against hCA II, were chosen and docked at the binding sites of these enzymes to explain the inhibitory activities of the series. The newly synthesized compounds presented satisfactory pharmacokinetic properties via the estimation of ADME properties.

New halogenated chalcones with cytotoxic and carbonic anhydrase inhibitory properties: 6-(3-Halogenated phenyl-2-propen-1-oyl)-2(3H)-benzoxazolones.

In this study, novel halogenated chalcones, 6-(3-halogenated phenyl-2-propen-1-one)-2(3H)-benzoxazolones (2a-n), were synthesized for the first time (except 2a), and their chemical structures were characterized by 1 H nuclear magnetic resonance (NMR), 13 C NMR, and high-resolution mass spectrometry spectra. Cytotoxic activities and carbonic anhydrase (CA) inhibitory effects of the compounds were studied to identify new possible drug candidate molecules. Cytotoxicity results pointed out that compound 2m, 6-[3-(3-bromophenyl)-2-propenoyl]-2(3H)-benzoxazolone, had the highest cytotoxicity (CC50 ) and potency selectivity expression (PSE) values. Thus, compound 2m can be considered as a lead compound of the series in terms of cytotoxicity. When the CA inhibition results of the compounds were evaluated, it was found that the Ki values of the compounds ranged from 30.5 ± 11.3 to 65.5 ± 25.6 µM toward hCA I, and they ranged from 7.3 ± 1.8 to 58.8 ± 12.3 µM toward hCA II. However, the Ki values of the reference drug, acetazolamide (AZA), were 30.2 ± 7.8 and 4.4 ± 0.6 µM toward hCA I and hCA II, respectively. According to the results obtained, compounds 2a-n had lower Ki values than AZA, whereas compounds 2a, 2b, 2e-g, 2l, and 2n had similar Ki values, compared with AZA. So, the compounds 2a, 2b, 2e-g, 2l, and 2n can be considered as lead molecules of this series for further considerations.

Synthesis of 4'-hydroxy-3'-piperidinomethylchalcone derivatives and their cytotoxicity against PC-3 cell lines.

A new series of mono Mannich bases of 4'-hydroxychalcones 2a-e carrying a variety of aryl groups was synthesized and the in vitro cytotoxic activities of the new compounds were screened against PC-3 cell lines. Bioactivities of 2a-e, which are reported for the first time in this study, were compared against their precursor 4'-hydroxychalcones 1a-e. Compound 2b was found to be the most potent (IC(50 )= 3.7 microM) among the compounds synthesized. In addition, the compounds 1a-c and 2d showed moderate cytotoxicity. Incorporation of the 3'-piperidinomethyl group in 1b and 1d raised the potency by 1.68 and 2.19 times respectively and, therefore, seemed to be a noteworthy molecular modification. Correlations were noted between cytotoxicity and one or more physiochemical constants of the aryl ring as well as log P values for the compounds 2a-e. The significant improvement of cytotoxicity of 2b, 2d, and 2e against PC-3 cell lines compared with their chalcone precursors suggests that the incorporation of a piperidinomethyl group is a useful molecular modification and further development of these compounds as candidate cytotoxic agents may be warranted.