Probing sulphamethazine and sulphamethoxazole based Schiff bases as urease inhibitors; synthesis, characterization, molecular docking and ADME evaluation.

In the current study, a novel series of Schiff base derivatives of (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (3a-3f) and (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (3g-3q) were synthesize. The structures of synthetic compounds were elucidated by various spectroscopic techniques such as FTIR, NMR and spectrometric HRMS analysis. Synthetic derivatives were evaluated for their Jack Bean urease inhibitory activity using established in-vitro assay. It is worth mentioning here that most of our derivatives of both series displayed moderate to strong inhibitory activity, ranging between IC50 = 2.48 ± 0.78 µM and 35.63 ± 1.26 µM, as compared to standard thiourea (IC50 = 20.03 ± 2.03 µM). Further, structure activity relationship studies suggest that the presence of halogen at ortho and para positions on the aryl ring in (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide derivatives and hydroxy and halogen in (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide derivatives increased the urease inhibitory activity. Furthermore, molecular docking studies were carried out in order to investigate the binding mode of this class of compounds to urease. In order to evaluate drug likeness of compounds ADME evaluation was done, and the synthesized compounds were found to be non-toxic and present passive gastrointestinal absorption. The data suggests the synthesized sulphamethazine and sulphamethoxazole derivatives can serve as a novel scaffold to inhibit urease.

A new Schiff base copper(II) complex induces cancer cell growth inhibition and apoptosis by multiple mechanisms.

A new Schiff base copper(II) complex [N,N'-bis(2'-hydroxyphenylacetone)-o-ethanediamine] copper (II) (M1) has been synthesized and characterized by single X-ray crystallography. The cytotoxicity of complex M1 was evaluated against HeLa, LoVo, A549, A549/cis cancer cell lines, and the normal cell lines LO2 and HUVEC, by MTT (3-(4,5-dimethylthiazoyl-2-yl)2,5-diphenyltetrazoliumbromide) assays. The IC50 (50% inhibition concentrations) is in the range of 5.13-11.68 µM, which is somewhat lower than cisplatin on the basis of platinum molar concentration. Furthermore, anticancer mechanistic studies showed that the complex M1 inhibited cell proliferation by blocking DNA synthesis and then acted on nuclear division of HeLa cells over time. Moreover, M1 increased intracellular ROS (Reactive oxygen species) levels in a dose-dependent manner. Western blot analysis indicated M1 dramatically decrease c-Myc transcription factor and KLF5 (Krüppel-like factor 5) protein expression levels in HeLa. M1 did not inhibit proteasomal activity. Finally, M1 induced DNA damages and activated the DNA damage repair pathways.

Schiff bases of 4-Phenyl-2-Aminothiazoles as hits to new antischistosomals: Synthesis, in vitro, in vivo and in silico studies.

The treatment of schistosomiasis is based on a single drug, the praziquantel (PZQ), an oral bioavailable and efficient agent which causes minimal side effects. The main concern about this approach, however, is that relying on only one drug to treat a helminthic disease is a dangerous strategy since history shows that pathogens easily evolve to resistant forms. Actually, reports about experimental strains exhibiting low sensibility to PZQ can be found in literature. The search for new antischistosomals, consequently, is urgent. Here we report the synthesis of seventeen Schiff bases of 4-(4-Substituted phenyl)-N-(4-substituted benzylidene)thiazole-2-amines which were tested in vitro and in vivo against Schistosoma mansoni adult worms. Moreover, in silico studies to propose potential macromolecular targets and to predict the oral bioavailability were also performed. The analog GPQF-108 exhibited the best in vitro performance (IC50: 29.4 µM, SI:6.1) associated with promising in vivo activity, with a significant decrease in the adult life forms and oviposition. Oral bioavailability could be impaired by the predicted low water solubility of GPQF-108, although it also exhibited good membrane permeability. The water solubility, however, could be improved by decreasing the particles size. Serine/Threonine- and Tyrosine Kinases, Carbonic Anhydrase, Tyrosine Phosphatase and Arginase were predicted as potential macromolecular targets through which the GPQF-108 could be acting against the helminth. This class of compounds exhibited an interesting initial therapeutic profile with the advantage of being chemically diverse from the PZQ and be easily synthesized from commercial reagents which could lead to low-cost drugs. These aspects make this class of compounds interesting hits to be explored against schistosomiasis.

Injectable Schiff base polysaccharide hydrogels for intraocular drug loading and release.

A novel voriconazole (VCZ)-loaded injectable hydrogel was in situ synthetized via a Schiff base reaction between polyaldehyde dextran (PAD) and carboxymethyl chitosan (CMCTS) for intraocular drug loading and release. Water-insoluble VCZ, which is an effective agent in clinic treating fungal endophthalmitis, was loaded through the inclusion into the ß-cyclodextrin (ß-CD) cavity based on host-guest interaction on the linear poly ß-CD chain, which was in situ twined in the cross-linked hydrogel structure. The gelation time, degradation, and drug release process were investigated by studying three kinds of hydrogels with different volume ratio of PAD to CMCTS resolving in phosphate buffered saline (PBS) solution (3:7, 6:7, 9:7), respectively. The property of VCZ-loaded injectable hydrogel should be adjusted through changing the cross-linked density of the hydrogel, the molecular weight or concentration of the linear poly ß-CD to meet the treating requirement, and a multistage drug controlled-release mechanism was proposed. In conclusion, the VCZ-loaded in situ injectable hydrogel should be offered as a promising strategy for intraocular drug delivery in vitreous cavity for the treatment of fungal endophthalmitis. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1909-1916, 2019.

A novel approach towards design, synthesis and evaluation of some Schiff base analogues of 2-aminopyridine and 2-aminobezothiazole against hepatocellular carcinoma.

Hepatocellular carcinoma is the most common primary malignancy of the liver with poor prognosis. In this study novel, Schiff's bases of 2-aminopyridine (SSSC-26 to 31) and 2-aminobenzothiazole (SSSC-32 to 37) were designed, synthesised and evaluated for antioxidant potential using DPPH method, and anti-hepatocellular carcinoma property using diethylnitrosamine (DEN) induced hepatocellular carcinoma rat model. The in-silico pharmacokinetic, rule of five and toxicity studies reveals that all the leads have an excellent intrinsic quality and sufficient structural features necessary for an oral activity. Molecular docking studies of all compounds into the ligand binding pocket of checkpoint kinase1 and vascular endothelial growth factor receptor-2 was also performed using Schrodinger software suite v8.5, and which have shown good Glide scores. Further compounds were synthesised based on the docking score and ADMET profile. The 1,1-diphenyl-2-picrylhydrazil (DPPH) scavenging study was carried out, and results showed that SSSC-29 (IC50-63.60) and SSSC-33 (IC50-60.32) were having good anti-oxidant potential in comparison with ascorbic acid (IC50-55.27). SSSC-33 further evaluated for anti-cancer potential against diethylnitrosamine (200mg/kg bw) induced hepatocellular carcinoma in rats. The biochemical, histopathological and morphological data showed that SSSC-33 can reverse the changes occurred in the cancerous liver significantly. All these findings suggested that SSSC-33-((benzo[d]thiazol-2-ylimino) methyl)phenol) could be a potential compound in combating the oxidative damage of hepatic cells occurred due to the development of hepatocellular carcinoma induced by a chemical carcinogen, DEN.

Evaluation of cellular uptake, cytotoxicity and cellular ultrastructural effects of heteroleptic oxidovanadium(IV) complexes of salicylaldimines and polypyridyl ligands.

Searching for prospective vanadium-based drugs for cancer treatment, a new series of structurally related [VIVO(L-2H)(NN)] compounds (1-8) was developed. They include a double deprotonated salicylaldimine Schiff base ligand (L-2H) and different NN-polypyridyl co-ligands having DNA intercalating capacity. Compounds were characterized in solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate and bind through both nitrogen donor atoms in an axial-equatorial mode. The cytotoxicity was evaluated in human tumoral cells (ovarian A2780, breast MCF7, prostate PC3). The cytotoxic activity was dependent on type of cell and incubation time. At 24h PC3 cells presented low sensitivity, but at 72h all complexes showed high cytotoxic activity in all cells. Human kidney HEK293 and ovarian cisplatin resistant A2780cisR cells were also included to evaluate selectivity towards cancer cells and potency to overcome cisplatin resistance, respectively. Most complexes showed no detectable interaction with plasmid DNA, except 2 and 7 which depicted low ability to induce single strand breaks in supercoiled DNA. Based on the overall cytotoxic profile, complexes with 2,2´-bipyridine and 1,10-phenanthroline ligands (1 and 2) were selected for further studies, which consisted on cellular distribution and ultrastructural analyses. In the A2780 cells both depicted different distribution profiles; the former accumulates mostly at the membrane and the latter in the cytoskeleton. Morphology of treated cells showed nuclear atypia and membrane alterations, more severe for 1. Complexes induce different cell death pathways, predominantly necrosis for 1 and apoptosis for 2. Complexes alternative mode of cell death motivates the possibility for further developments.

Synthesis, structure, protein binding of Cu(II) complexes with a tridentate NNO Schiff-base ligand.

Four new Cu(II) complexes (1, 2, 3 and 4) in the presence of different anions (Cl(-), Br(-), I(-) and ClO4(-)) have been prepared by tridentate NNN Schiff-base ligand (N,N-dimethyl-N'-[phenyl(2-pyridyl)methylene]ethane-1,2-diamine) and well characterized by single-crystal X-ray diffraction, elemental analysis, IR and UV-Vis spectroscopy. The interactions of complexes 1-4 with human serum albumin (HSA) have been investigated in Tris-HCl buffer solution at pH 7.4 by spectroscopic methods and a molecular docking technique. Experimental results proved that the four complexes quench the fluorescence of HSA through a static quenching mechanism. Thermodynamic parameters were calculated from Van't Hoff equation. The distance r between the donor (HSA) and acceptor (complexes 1-4) has been obtained by means of Förester resonance energy transfer (FRET). Molecular docking results indicated that the main active binding sites for complexes 1, 2 and 4 are site III in subdomain IB and for complex 3 is site II in subdomain III A. The combination of molecular docking results and fluorescence experimental results indicate that the interaction between 1-4 and HSA are dominated by hydrophobic forces as well as hydrogen bonds.

Structural characterization of new Schiff bases of sulfamethoxazole and sulfathiazole, their antibacterial activity and docking computation with DHPS protein structure.

New Schiff bases (1, 2) of substituted salicylaldehydes and sulfamethoxazole (SMX)/sulfathiazole (STZ) are synthesized and characterized by elemental analysis and spectroscopic data. Single crystal X-ray structure of one of the compounds (E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (1c) has been determined. Antimicrobial activities of the Schiff bases and parent sulfonamides (SMX, STZ) have been examined against several Gram-positive and Gram-negative bacteria and sulfonamide resistant pathogens; the lowest MIC is observed for (E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-N-(thiazol-2-yl)benzene sulfonamide (2c) (8.0 µg mL(-1)) and (E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-N-(5-methylisoxazol-3-yl)benzene sulfonamide (1c) (16.0 µg mL(-1)) against sulfonamide resistant pathogens. DFT optimized structures of the Schiff bases have been used to carry out molecular docking studies with DHPS (dihydropteroate synthase) protein structure (downloaded from Protein Data Bank) using Discovery Studio 3.5 to find the most preferred binding mode of the ligand inside the protein cavity. The theoretical data have been well correlated with the experimental results. Cell viability assay and ADMET studies predict that 1c and 2c have good drug like characters.

In vitro and in vivo structure-property relationship of (68)Ga-labeled Schiff base derivatives for functional myocardial pet imaging.

PURPOSE: SPECT (e.g., with (99m)Tc-sestamibi) is routinely used for imaging myocardial damage, even though PET could offer a higher spatial resolution. Using the generator-gained isotope (68)Ga would allow a rapid supply of the tracer in the diagnostic unit. For this reason, the aim of the study was to develop (68)Ga-labeled PET tracers based on different Schiff base amines and to evaluate the cardiomyocyte uptake in vitro as well as the biodistribution of the tracers in vivo. PROCEDURES: Fifteen different Schiff bases (basing on 3 different backbones) were synthesized and labeled with (68)Ga. Lipophilicity varied between 0.87 ± 0.24 and 2.72 ± 0.14 (logD value). All tracers were positively charged and stable in plasma and apo-transferrin solution. In vitro uptake into cardiomyocytes was assessed in HL-1 cells in the absence and presence of the ionophor valinomycin. In vivo accumulation in the heart and in various organs was assessed by small animal PET imaging as well as by ex vivo biodistribution. The results were compared with (99m)Tc-sestamibi and (18)F-flurpiridaz. RESULTS: All cationic Schiff bases were taken up into cardiomyocytes but the amount varied by a factor of 10. When destroying the membrane potential, the cellular uptake was markedly reduced in most of the tracers, indicating the applicability of these tracers for identifying ischemic myocardium. PET imaging revealed that the in vivo myocardial uptake reached a constant value approximately 10 min after injection but the intracardial amount of the tracer varied profoundly (SUV 0.46 to 3.35). The most suitable tracers showed a myocardial uptake which was comparable to that of (99m)Tc-sestamibi. CONCLUSIONS: (68)Ga-based Schiff bases appear suitable for myocardial PET images with uptake comparable to (99m)Tc-sestamibi but offering higher spatial resolution. By systematical variation of the backbone and the side chains, tracers with optimal properties can be identified for further clinical evaluation.

Synthesis, characterization and biological activity of Schiff base analogues of indole-3-carboxaldehyde.

Eight novel heterocyclic Schiff bases derived from the condensation reactions of indole 3-carboxaldehyde with different l-amino acids (histidine, glutamic acid, aspartic acid, leucine, valine) as well as with some aminophenols, have been synthesized and characterized by various spectroscopic methods (IR, MS, (1)H NMR). Schiff base derivatives of indole 3-carboxaldehyde were labeled with (99m)Tc and radiochemical purity was above 97% which is ascertained by instant thin layer chromatography using different solvent conditions. Stability studies of all the derivatives of indole 3-carboxaldehyde was determined under physiological conditions and were stable for more than 24h. Blood clearance showed a quick wash out from the circulation and biological half life was found to be t((1/2))(F)=1h 15min; t((1/2))(S)=10h 05min. Excellent quality radioimages of tumor bearing mice were recorded showing rapid clearance of background activity, visualization of tumor at 3h and clearance from kidneys of histidine analogue which was further evidenced in biodistribution studies. Antimicrobial activity of these Schiff base compounds was evaluated against Bacillus subtilis, Pseudomonas fluorescence, Staphylococcus aureus, Aspergillus niger, Candida albicans and Trichophyton rubrum.

Synthesis and biodistribution of six novel 99mTc complexes of 2-hydroxybenzaldehyde-amino acid Schiff bases.

For the purpose of developing novel diagnostic pharmaceuticals of 99mTc-labeled small-size complexes, six novel complexes of 99mTc-2-hydroxybenzaldehyde-amino acid Schiff bases were designed and synthesized, and their biodistributions in mice were investigated. All the compounds were obtained in radiochemical yields higher than 90% at optimal conditions, and poor uptakes in muscle, brain, heart and tumor were commonly observed with rapid blood clearance. Potentiality was revealed of good kidney imaging by 2-hydroxybenzaldehyde-alanine (L2) complex within 40 min post-injection. Good bone uptake of 2-hydroxybenzaldehyde-histidine (L4) and 2-hydroxybenzaldehyde-aspartic acid (L5) complexes, high spleen accumulation of 2-hydroxybenzaldehyde-glycine (L1) and 2-hydroxybenzaldehyde-cysteine (L3) complexes, and non-specific biodistribution of 2-hydroxybenzaldehyde-glutamic acid (L6) complex were demonstrated.

Preparation and characterization of technetium complexes with Schiff base and phosphine coordination. 1. Complexes of technetium-99g and -99m with substituted acac2en and trialkyl phosphines (where acac2en = N,N'-ethylenebis[acetylacetone iminato]).

A series of 23 technetium(III) complexes of the type [TcL(PR3)2]+, where L represents a tetradentate Schiff base ligand in the equatorial plane and PR3 represents the axial phosphine ligands, are reported. Full ligand syntheses and characterizations are included. The technetium complexes were prepared with 99mTc to study the organ distribution in guinea pigs at 5 and 60 min postinjection. Four prototypical complexes of the series were also prepared with either 99gTc or 99gTc/99mTc (designated as carrier-added) to allow macroscopic characterization. Equivalence of the 99gTc and 99mTc complexes was demonstrated by dual detection high performance liquid chromatography (HPLC) techniques. The development of a one-step preparation from the standard two-step method is discussed for some complexes. Biodistribution data are related to structure and lipophilicity. None of the complexes in the series exhibited a tendency for in vivo reduction. Myocardial uptake was favorable for a number of complexes. The optimal agent from this series for further imaging development was chosen based on myocardial uptake, rapid blood and liver clearance, and ability to be formulated as a one-step kit.

Synthesis, characterization and biodistribution of new 99mTc oxo and nitrido complexes with bi- and tetradendate unsaturated NS and N2S2 Schiff bases derived from 2-aminocyclopentene-1-dithiocarboxylic acid as potential heart imaging agents.

The synthesis, characterization and 99mTc labelling of unsaturated diamino dithiol ligands with methyl dithiocarboxylate functions: 2-aminocyclopentene-1-dithiocarboxylic methyl ester (H2L1), N,N'-ethylene bis(methyl 2-aminocyclopentene-1-dithiocarboxylate) (H2L2) and N,N'-propylene bis (methyl 2-aminocyclopentene-1-dithiocarboxylate) (H2L3) are described. Cationic oxo (Tc = O) and neutral nitrido (Tc = N) complexes were obtained. Biodistribution studies in rat showed a good heart uptake of 99mTcN-L2 (2% ID at 5 min) with a high heart-to-blood ratio (5.8 at 5 min), but this complex also exhibited high lung and liver uptake.