Optimization and Comparison of Synthetic Procedures for a Group of Triazinyl-Substituted Benzene-Sulfonamide Conjugates with Amino Acids.

Sulfonamides incorporating 1,3,5-triazine moieties can selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII, and XIV over cytosolic isoforms I and II. In the present work, a highly effective synthetic procedure was proposed for this group of potent cancerostatic drugs and compared with previously used methods. The synthesis of triazinyl-substituted benzene-sulfonamide conjugates with amino acids can be easily carried out using sodium carbonate-based water solution as a synthetic medium instead of N,N-Diisopropylethylamine/Dimethylformamide. The benefits of this synthetic procedure include: (i) high selectivity of the creation of disubstituted conjugates; (ii) several times higher yield (≥95%) than that achieved previously; (iii) elimination of organic solvents by the use of an environmental friendly water medium (green chemistry); (iv) simple and fast isolation of the product. The synthesis and resulting products were evaluated using TLC, IR, NMR, and MS methods. The present work demonstrates a significant advantage in providing shortened routes to target structures.

Design and Antiproliferative Evaluation of Novel Sulfanilamide Derivatives as Potential Tubulin Polymerization Inhibitors.

A series of sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, MCF-7 and PC-3). The detailed structure-activity relationships for these sulfanilamide-1,2,3-triazole hybrids were investigated. All these sulfanilamide-1,2,3-triazole hybrids exhibited moderate to potent activity against all cell lines. In particular 4-methyl-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (11f) showed the most potent inhibitory effect against PC-3 cells, with an IC50 value of 4.08 µM. Furthermore, the tubulin polymerization inhibitory activity in vitro of compound 11f was 2.41 µM. These sulfanilamide hybrids might serve as bioactive fragments for developing more potent antiproliferative agents.

Synthesis of Canthardin Sulfanilamides and Their Acid Anhydride Analogues via a Ring-Opening Reaction of Activated Aziridines and Their Associated Pharmacological Effects.

The cantharidinimide derivatives, 5a-h, including sulfanilamides containing pyrimidyl, pyrazinyl, hydrogen, thiazolyl, and oxazolyl groups were synthesized. Modification of cantharidinimide by means of the reaction of activated aziridine ring opening led to the discovery of a novel class of antitumor compounds. The analogues 10i-k, 11l-n, 12o-p, and 16q-s were obtained from treating cantharidinimide 6 and analogues (7, 8, and 13) with activated aziridines, which produced a series of ring-opened products including normal and abnormal types. Some of these compounds showed cytotoxic effects in vitro against HL-60, Hep3B, MCF7, and MDA-MB-231 cancer cells. The most potent cytostatic compound, N-cantharidinimido-sulfamethazine (5a), exhibited anti-HL-60 and anti-Hep3B cell activities. Two compounds 5g and 5h displayed slight effects on the Hep3B cell line, while the other compounds produced no response in these four cell lines.

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-SUBSTITUED 4-THIAZOLIDINONES WITH SULFANILAMIDE PHARMACOPHORE.

After incorporation pharmacophores of allylamine and sulfanilamide into 4-thiazolidinone's ring - no antimicrobial activity was determined. This outcome stimulated synthesis of new group - 5-substituted 4-thiazolidinones. In the literature it is noted that the fragment of aldehyde in 5 position of 4-thiazolidinone's ring should give or increase biological activity. So, it was decided to incorporate fragment of aldehyde into 4-thiazolidinone's ring together with sulfanilamide pharmacophore, investigate antimicrobial activity and compare it with initial compounds - sulfanilamides. It was established that new compounds suppressed growth of S. arteus, E. coli, B. subtilis, P. mirabilis, C. albicans. Sulfanilamide, sulfapyridine and/or 2-chlorobenzaldehyde were incorporated into the structure of the most active compounds. It was concluded that synthesis of 4-thiazolidinones substituted by aldehyde in 5 position and sulfanilamide in 2 position are not potential antimicrobial agents.

One-step synthesis of azole- and benzazole-based sulfonamides in aqueous media.

Several benzazoles (benzoxazoles, benzothiazoles, and benzimidazoles) and azoles (1H-1,2,4-triazole-5(4H)-thiones and 1,2,4-oxadiazoles) bearing a sulfonamide moiety were efficiently prepared via the reactions of dimethyl (arylsulfonyl) dithioimidocarbonate derivatives and their 2-aminobenzene precursors, thiosemicarbazides, and amidoximes, respectively, in the presence of K(2)CO(3) as a base in aqueous ethanol (25%) as a green media in moderate to excellent yields.

Synthesis and carbonic anhydrase I, II, IX and XII inhibition studies of 4-N,N-disubstituted sulfanilamides incorporating 4,4,4-trifluoro-3-oxo-but-1-enyl, phenacylthiourea and imidazol-2(3H)-one/thione moieties.

A series of sulfonamides incorporating the sulfanilamide (SA) scaffold were prepared. Reaction of the 4-amino moiety of SA with benzyl chlorides or substituted bromoacetophenones afforded the 4-mono-alkylated derivatives which were then reacted with 1,1,1-trifluoro-4-isobutoxybut-3-en-2-one leading to a series of 4-N,N-disubstituted SAs. The key intermediates were also reacted with ethoxycarbonyl isothiocyanate leading to thioureas or were cyclized in the presence of potassium cyanate/isothiocyanate to the corresponding imidazol-2(3H)-one/thiones. The new compounds were tested as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, and the transmembrane, tumor-associated CA IX and XII. These sulfonamides were ineffective CA I and II inhibitors but were nanomolar CA IX and XII inhibitors, making them of interest as clinical candidates for antitumor/antimetastasis applications.

Inhibition studies of new ureido-substituted sulfonamides incorporating a GABA moiety against human carbonic anhydrase isoforms I-XIV.

Reaction of γ-Boc-GABA, prepared by protecting the γ-amino moiety of the amino butyric acid with the tert-butyloxycarbonyl (Boc) protecting group, with 4-methyl/ethyl benzenesulfonamide, followed by removal of the Boc protecting group in 3 M HCl afforded the corresponding hydrochlorides, which were further derivatized by reaction with a varying of aryl isocyanates to give a new classes of ureido substituted benzenesulfonamide containing a GABA moiety. Inhibition studies of the human carbonic anhydrase(CA, EC 4.2.1.1) isoforms, CA I­XIV with these new compounds revealed that they possess moderate-weak inhibition potency against hCA III, IV, VA, VI and XIII, rather efficient inhibitory power against hCA I, VI, and IX, and excellent inhibition of the physiologically relevant hCA II and VII, as well as of the two tumor-associated isoforms CA IX and XII. The inhibition profile of the new ureido-substituted benzenesulfonamides reported here is thus very different from the corresponding ureido-substituted analogs incorporating sulfanilamide, which were previously investigated as inhibitors of some of these enzymes.

3D-QSAR CoMFA studies on sulfonamide inhibitors of the Rv3588c ß-carbonic anhydrase from Mycobacterium tuberculosis and design of not yet synthesized new molecules.

The human pathogen Mycobacterium tuberculosis contains three ß-carbonic anhydrases (CAs, EC 4.2.1.1) in its genome. Inhibition of some of these CAs was shown to modulate the growth of M. tuberculosis. 3D-QSAR Comparative molecular field analyses (CoMFA) were carried out on inhibitors of the enzyme Rv3588c (also denominated mtCA 2). A series of sulfonamides known to inhibit mtCA 2, including some diazenylbenzenesulfonamides, was considered in our study. The predictive ability of the model was assessed using a test set of seven compounds. The best model has demonstrated a good fit having predictive r(2) value of 0.93 and cross-validated coefficient q(2) value as 0.88 in tripos CoMFA region. Our results indicate that the steric and electrostatic factors play a significant role in mtCA 2 inhibition for the investigated compounds. We proposed nine new not yet synthesized mtCA 2 inhibitors, all of them probably with significantly improved anti-Rv3588c inhibitory activity.

Sulfa and trimethoprim-like drugs - antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors.

Recent advances in microbial genomics, synthetic organic chemistry and X-ray crystallography provided opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics in clinical use for decades. The antimetabolites, sulfa drugs and trimethoprim (TMP)-like agents, are inhibitors of three families of enzymes. One family belongs to the carbonic anhydrases, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase. The antibacterial agents belonging to the THF and DHPS inhibitors were developed decades ago and present significant bacterial resistance problems. However, the molecular mechanisms of drug resistance both to sulfa drugs and TMP-like inhibitors were understood in detail only recently, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families.

Design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines as novel p53-MDM2 inhibitors.

A series of sulfamide and triazole benzodiazepines were obtained with the principle of bioisosterism. The p53-murine double minute 2 (MDM2) inhibitory activity and in vitro antitumor activity were evaluated. Most of the novel benzodiazepines exhibited moderate protein binding inhibitory activity. Particularly, triazole benzodiazepines showed good inhibitory activity and antitumor potency. Compound 16 had promising antitumor activity against the U-2 OS human osteosarcoma cell line with an IC50 value of 4.17 µM, which was much better than that of nutlin-3. The molecular docking model also successfully predicted that this class of compounds mimicked the three critical residues of p53 binding to MDM2.

Inhibition of human carbonic anhydrase isoforms I-XIV with sulfonamides incorporating fluorine and 1,3,5-triazine moieties.

Reaction of cyanuryl fluoride with sulfanilamide or 4-aminoethylbenzenesulfonamide afforded triazinyl-substituted benzenesulfonamides incorporating fluorine, which were further derivatized by reaction with amines, amino alcohols, amino acids or amino acid esters. Inhibition studies of all the human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, hCA I-XIV with these compounds revealed that they show moderate-weak inhibition of hCA III, IV, VA and XIII, rather moderate inhibition against hCA I, VI, and IX, and excellent inhibition of the physiologically relevant hCA II, VII and XII. The inhibition profile of these fluorine containing triazinyl sulfonamides is thus very different from the corresponding analogs incorporating chlorine, which were previously investigated as inhibitors of some of these enzymes.

Dihalogenated sulfanilamides and benzolamides are effective inhibitors of the three ß-class carbonic anhydrases from Mycobacterium tuberculosis.

A series of halogenated sulfanilamides and halogenated benzolamide derivatives have been investigated as inhibitors of three ß-carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Mycobacterium tuberculosis, mtCA 1 (Rv1284), mtCA 2 (Rv3588c) and mtCA 3 (Rv3273). All three enzymes were inhibited with efficacies between the submicromolar to the micromolar one, depending on the substitution pattern at the sulfanilamide moiety/fragment of the molecule. Best inhibitors were the halogenated benzolamides (K(I)s in the range of 0.12-0.45 µM) whereas the halogenated sulfanilamides were slightly less inhibitory (K(I)s in the range of 0.41-4.74 µM). This class of ß-CA inhibitors may have the potential for developing antimycobacterial agents with a diverse mechanism of action compared to the clinically used drugs for which many strains exhibit multi-drug/extensive multi-drug resistance.

Structure-based design and biochemical evaluation of sulfanilamide derivatives as hepatitis B virus capsid assembly inhibitors.

Virus capsid structure is essential in virion maturation and durability, so disrupting capsid assembly could be an effective way to reduce virion count and cure viral diseases. However, currently there is no known antiviral which affects capsid inhibition, and only a small number of assembly inhibitors were experimentally successful. In this present study, we aimed to find hepatitis B virus (HBV) capsid assembly inhibitor which binds to the HBV core protein and changes protein conformation. Several candidate molecules were found to bind to certain structure in core protein with high specificity. Furthermore, these molecules significantly changed the protein conformation and reduced assembly affinity of core protein, leading to decrease of the number of assembled capsid or virion, both in vitro and in vivo. In addition, prediction also suggests that improvements in inhibition efficiency could be possible by changing functional groups and ring structures.

Inhibition of the alpha- and beta-carbonic anhydrases from the gastric pathogen Helycobacter pylori with anions.

The gastric pathogen Helicobacter pylori encodes two carbonic anhydrases (CAs, EC 4.2.1.1), an α- and a ß-class one, hpαCA and hpßCA, crucial for its survival in the acidic environment from the stomach. Sulfonamides, strong inhibitors of these enzymes, block the growth of the pathogen, in vitro and in vivo. Here we report the inhibition of the two H. pylori CAs with inorganic and complex anions and other molecules interacting with zinc proteins. hpαCA was inhibited in the low micromolar range by diethyldithiocarbamate, sulfamide, sulfamic acid, phenylboronic acid, and in the submillimolar one by cyanide, cyanate, hydrogen sulfide, divanadate, tellurate, perruthenate, selenocyanide, trithiocarbonate, iminodisulfonate. hpßCA generally showed a stronger inhibition with most of these anions, with several low micromolar and many submillimolar inhibitors detected. These inhibitors may be used as leads for developing anti-H. pylori agents with a diverse mechanism of action compared to clinically used antibiotics.

Study of the interaction between sodium salts of (2E)-3-(4'-halophenyl)prop-2-enoyl sulfachloropyrazine and bovine serum albumin by fluorescence spectroscopy.

Three sodium salts of (2E)-3-(4'-halophenyl)prop-2-enoyl sulfachloropyrazine (CCSCP) were synthesized and their structures were determined by (1)H and (13)C NMR, LC-MS and IR. The binding properties between CCSCPs and bovine serum albumin (BSA) were studied using fluorescence spectroscopy in combination with UV-vis absorbance spectroscopy. The results indicate that the fluorescence quenching mechanisms between BSA and CCSCPs were static quenching at low concentrations of CCSCPs or combined quenching (static and dynamic) at higher CCSCP concentrations of 298, 303 and 308 K. The binding constants, binding sites and corresponding thermodynamic parameters (ΔH, ΔS, ΔG) were calculated at different temperatures. All ΔG values were negative, which revealed that the binding processes were spontaneous. Although all CCSCPs had negative ΔH and positive ΔS, the contributions of ΔH and ΔS to ΔG values were different. When the 4'-substituent was fluorine or chlorine, van der Waals interactions and hydrogen bonds were the main interaction forces. However, when the halogen was bromine, ionic interaction and proton transfer controlled the overall energetics. The binding distances between CCSCPs and BSA were determined using the Förster non-radiation energy transfer theory and the effects of CCSCPs on the conformation of BSA were analyzed by synchronous fluorescence spectroscopy.

Synthesis and antidiabetic performance of ß-amino ketone containing nabumetone moiety.

We wish to report the further design and improved synthesis that resulted in two series of target molecules, TM-1 and TM-2, with remarkably simplified structures containing ß-amino ketone of discrete nabumetone moiety. These were obtained via a 'one-pot, two-step, three-component' protocol of Mannich reaction with yield up to 97%. A total of 28 out of 31 new compounds were characterized using (1)H NMR, (13)C NMR, ESI MS and HRMS techniques. Studies on their antidiabetic activities, screened in vitro at 10 µg mL(-1) level, indicate that TM-2 possesses peroxisome proliferator-activated receptor activation and α-glucosidase inhibition activity significantly stronger than that of TM-1, and also that of the series B compounds that were previously synthesized by the group. Analysis of the structure-activity relationship points to the sulfanilamide unit as the most probable potent group of ß-amino ketone and, on the basis of which, a tangible strategy is presented for the development of new antidiabetic drugs.

Synthesis and in vitro antimicrobial study of 4-thiazolidinone containing sulfanilamide.

The title compounds, 3-allyl-2-sulfanylamido-4-thiazolidinones (2a-d), have been synthesized after substitution of amino group of sulfanylamide with allylisothiocyanate and cyclization into 4-thiazolidinones. The synthesized compounds were tested for their antibacterial and antifungal activity (MIC) in vitro) against microorganisms: S. aureus, E. faecalis. E. coli, P. aeruginosa, K. pneumoniae, P. mirabilis, B. subtilis, B. cereus and C. albicans taking sulfadimidine, sulfathiazole, sulfanilamide and sulfamethizole as standard drugs. Synthesized compounds (2a-d) demonstrated selective activity against B. cereus.

Synthesis of sulfanilamide derivatives and investigation of in vitro inhibitory activities and antimicrobial and physical properties.

Novel sulfanilamide derivatives were synthesized and evaluated for carbonic anhydrase inhibitory activity as a target for the treatment of glaucoma, and antibacterial properties for use in chemotherapy. Synthesized compounds were characterized by FT-IR, (1)H NMR, (13)C NMR and photoluminescence. In vitro inhibitory activities were measured by UV-Vis and some of the compounds were found have greater inhibitory effects than the lead compound sulfanilamide. The correlation between inhibitory activity, biological properties and the physicochemical properties of water solubility and partition coefficients was also investigated. Sulfanilamide derivatives gave intense emissions upon irradiation by UV light and a dimethyl substituted compound and a cyclic analog have photoluminescence quantum yields 42% and 31% and long excited-state lifetimes of 3.92 and 2.91 ns, respectively.

[Synthesis, spectroscopy and antibacterial activity of charge transfer complexes of heteropolytungstate containing sulfanilamide].

Two charge transfer complexes of heteropolytungstate with Keggin structure, (C6 H9 N2 O2S) 3PW12 O40 x 6H2O (SPW12) and (C6 H9 N2 O2S)4 SiW12 O40 x 5H2O (SSiW12) were synthesized with 12-tungstophosphoric (silicic) acid and sulfanilamide in aqueous phase. The title complexes were characterized by means of elementary analysis, FTIR, UV, 1H NMR, XRD and TG-DSC. The results indicate that the title complexes are new heteropoly compounds, and the UV results reveal that there is a charge transfer interaction between sulfanilamide and heteropoly anion. Thermal analysis shows that the process of mass loss of the title complexes is carried out in four stages, and the two complexes begin to decompose at 272.8 degrees C and 330.4 degrees C, respectively. The intermediates of the thermal decomposition were identified by FTIR Antibacterial test results show that the title complexes both have good antibacterial activity, and the inhibition rate of SPW12 to Escherichia coli, Staphylococcus aurous is 73.28% and 99.36%, respectively.

Preparation and spectroscopic characterization of novel cyclodiphosph(V)azane of N(1)-2-pyrimidinylsulfanilamide complexes. Magnetic, thermal and biological activity studies.

Hexachlorocyclophosph(V)azane of sulfadiazine, (sulfupyrimidine) [N(1)-2-pyrimidinylsulfanilamide] (H2L1), was prepared and reacted with sulfur and glycine to give (H2L2) and (H2L3) ligands, respectively. The prepared ligands; H2L1, H2L2 and H2L3, react in 1:2 [ligands]:[metal ions] molar ratio with transition metals to give coloured complexes in a relatively good yields. The complexes were characterized using different physicochemical techniques, namely elemental analyses, IR, UV-vis, mass, 1H NMR, molar conductance, magnetic, solid reflectance and thermal analysis. The spectral data reveal that all the ligands behave as neutral bidentate ligands and coordinated to the metal ions via pyrimidine-N and enolic sulfonamide OH. The molar conductance data reveal that the complexes are non-electrolytes while UV-vis, solid reflectance and magnetic moment data have been shown that the complexes have octahedral geometry. The thermal behaviour of the complexes is studied and the thermodynamic activation parameters are calculated. The ligands and their complexes show high to moderate bactericidal activity.