Synthesis, characterization, computational assay and anti-inflammatory activity of thiosemicarbazone derivatives: Highly potent and efficacious for COX inhibitors.

Multiple studies in the literature have demonstrated that synthetic compounds containing heterocyclic rings possess a reparative potential against acute and chronic inflammation. In the present study, two novel thiosemicarbazone derivatives based on l-ethyl-6-(thiophen-2-yl)indoline-2,3-dione with different phenyl substituted thiosemicarbazides were synthesized by condensation reaction and the structures of proposed target compounds (KP-2 and KP-5) were confirmed by UV-VIS, FTIR, 1H-NMR and 13C-NMR. In-vitro anti-inflammatory behavior of KP-2 and KP-5 was confirmed by bovine serum albumin (BSA) and ovine serum albumin (OSA) analysis. Acute and chronic anti-inflammatory potential of synthesized compounds were evaluated by using carrageenan and complete Freund's adjuvant (CFA) as inflammation-inducing agents, respectively. Inhibition of pro-inflammatory mediators and prevention of protein denaturation owing to synchronization of more electronegative flouro-groups substituted on phenyl rings along with heterocyclic indoline ring provides anti-inflammatory effects and are corroborated by radiological, histopathological analysis. Additional support was provided through density functional theory (DFT) and molecular docking. KP-5 exhibited excellent lead-likeness based on its physicochemical parameters, making it a viable drug candidate. The synthesized compounds also showed promising ADMET properties, enhancing their potential as therapeutic agents. These findings emphasize the pivotal role of new compounds for drug design and development.

Synthesis and evaluation of novel xanthene-based thiazoles as potential antidiabetic agents.

A series of xanthene-based thiazoles was synthesized and characterized by different scpectroscopic methods, i.e. Proton nuclear magnetic resonance (1 H NMR), carbon nuclear magnetic resonance (13 C NMR), infrared spectroscopy, carbon hydrogen nitrogen analysis, and X-ray crystallography. The inhibition potencies of 18 newly synthesized thiazole derivatives were investigated on the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase (α-Amy), and α-glycosidase (α-Gly) enzymes in accordance with their antidiabetic and anticholinesterase ability. The synthesized compounds have the highest inhibition potential against the enzymes at low nanomolar concentrations. Among the 18 newly synthesized molecules, 3b and 3p were superior to the known commercial inhibitors of the enzymes and have a much more effective inhibitory potential, with IC50 : 2.37 and 1.07 nM for AChE, 0.98 and 0.59 nM for BChE, 56.47 and 61.34 nM for α-Gly, and 152.48 and 124.84 nM for α-Amy, respectively. Finally, the optimized 18 compounds were subjected to molecular docking to describe the interaction between thiazole derivatives and AChE, BChE, α-Amy, and α-Gly enzymes in which important interactions were monitored with amino acid residues of each target enzyme.

Green Production and Interaction of Carboxylated CNTs/Biogenic ZnO Composite for Antibacterial Activity.

Using biomolecule-rich plant extracts, the conversion of metal ions to metal oxide nanoparticles via abiogenic approach is highly intriguing, environmentally friendly, and quick. The inherent inclination of plant extracts function as capping agents in the insitu synthesis. In this study, biogenic zinc oxide nanoparticles (ZnO-NPs) were synthesized using an aqueous leaf extract from Moringaoleifera. The ZnO-NPs were then mixed with carboxylated carbon nanotubes (CNTs) to create a carboxylated CNTs/biogenic ZnO composite using asol-gel method. The CNTs/ZnO composite displayed 18 mm, 16 mm, and 17 mm zones of inhibition (ZOI) against Bacillus cereus, Pseudomonas aeruginosa, and Escherichia coli, respectively. In contrast with ZnO-NPs, the produced carboxylated CNTs/ZnO composite demonstrated a 13 percent elevation in ZOI as antibacterial activity against Bacillus cereus ATCC 19659, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853. The characterization of ZnO-NPs and the carboxylated CNTs/ZnO composite were performed via FTIR, UV/Vis spectroscopy, SEM, and XRD. The XRD pattern depicted a nano-sized crystalline structure (Wurtzite) of ZnO-NPs and a carboxylated CNTs/ZnO composite. The current work comprehends a valuable green technique for killing pathogenic bacteria, and gives fresh insights into the manufacture of metal oxide composites for future research.

Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones.

Quinoxalin-2(1H)-one based design and synthesis produced several series of aldose reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values in the range of 0.032-0.468 µM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active. More significantly, most of the series 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 µM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 inhibitors having both potency for ALR2 inhibition and as antioxidants.

Chiral resolution, determination of absolute configuration, and biological evaluation of (1,2-benzothiazin-4-yl)acetic acid enantiomers as aldose reductase inhibitors.

A novel series of (1,2-benzothiazin-4-yl)acetic acid enantiomers was prepared by chiral resolution, and their absolute configurations were determined using the PGME method. The biological evaluation of the racemate and single enantiomers has shown a remarkable difference for the aldose reductase inhibitory activity and selectivity. The (R)-(-)-enantiomer exhibited the strongest aldose reductase activity with an IC(50) value of 0.120 µM, which was 35 times more active than the S-(+)-enantiomer. Thus, the stereocenter at the C4 position of this scaffold was shown to have a major impact on the activity and selectivity.

2-[(Z)-1,1-Dioxo-2-(2,4,5-tri-fluoro-benz-yl)-3,4-di-hydro-2H-1,2-benzo-thia-zin-4-yl-idene]acetic acid.

In the title compound, C17H12F3NO4S, the heterocyclic thia-zine ring adopts a half-chair conformation and the dihedral angle between the benzene rings is 43.28 (9)°. The α,ß-unsaturated C=C group is inclined at an angle of 21.0 (3)° to the benzene ring of the benzo-thia-zine moiety. In the crystal, inversion dimers linked by pairs of carb-oxy-lic acid O-H⋯O hydrogen bonds generate R 2 (2)(8) loops. Each of the F atoms accepts a Ca-H⋯F (a = aromatic) hydrogen bond from an adjacent mol-ecule, resulting in (001) sheets.

Copper-catalyzed asymmetric synthesis and comparative aldose reductase inhibition activity of (+)/(-)-1,2-benzothiazine-1,1-dioxide acetic acid derivatives.

A copper catalyst system for the asymmetric 1,4-hydrosilylation of the α,ß-unsaturated carboxylate class was developed by which synthesis of (+)- and (-)-enantiomers of 1,2-benzothiazine-1,1-dioxide acetates has been achieved with a good yield and an excellent level of enantioselectivity. A comparative structure-activity relationship study yielded the following order of aldose reductase inhibition activity: (-)-enantiomers > racemic > (+)-enantiomers. Further, a molecular docking study suggested that the (-)-enantiomer had significant binding affinity and thus increased inhibition activity.

Structure-activity relationships studies of quinoxalinone derivatives as aldose reductase inhibitors.

Novel quinoxalinone derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Among them, N1-acetate derivatives had significant activity in a range of IC50 values from low micromolar to submicromolar, and compound 15a bearing a C3-phenethyl side chain was identified as the most potent inhibitor with an IC50 value of 0.143 µM. The structure-activity studies suggested that both C3-phenethyl and C6-NO2 groups play an important role in enhancing the activity and selectivity of the quinoxalinone based inhibitors.

Bis[5-meth-oxy-2-(meth-oxy-carbon-yl)phen-yl] methyl-phospho-nate.

In the title phospho-nate, C19H21O9P, the dihedral angle between the benzene rings is 63.33 (3)°, and the P atom has a distorted tetra-hedral geometry, with angles in the range 101.30 (6)-120.38 (6)°. No significant inter-molecular inter-actions are observed in the crystal structure, and π-π inter-actions between symmetry-related benzene rings are beyond 4 Å.

Novel synthesis of nitro-quinoxalinone derivatives as aldose reductase inhibitors.

A novel, non-acid series of nitroquinoxalinone derivatives was synthesized and tested for their inhibitory activity against aldose reductase as targeting enzyme. All active compounds displayed an 8-nitro group, and showed significant activity in IC50 values ranging from 1.54 to 18.17 µM. Among them 6,7-dichloro-5,8-dinitro-3-phenoxyquinoxalin-2(1H)-one (7e), exhibited the strongest aldose reductase activity with an IC50 value of 1.54 µM and a good SAR (structure-activity relationship) profile.

Effect of C7 modifications on benzothiadiazine-1,1-dioxide derivatives on their inhibitory activity and selectivity toward aldose reductase.

The development and progression of chronic complications in diabetic patients, such as retinopathy, nephropathy, neuropathy, cataracts, and stroke, are related to the activation and/or overexpression of aldose reductase (ALR2), which is a member of the aldo-keto reductase superfamily. A structure-activity relationship study focused on the C7 position of 1,2,4-benzothiadiazine-1,1-dioxide derivatives was pursued in an attempt to discover ALR2 inhibitors with enhanced potency and selectivity. These studies led to a series of new C7-substituted compounds, which were evaluated for their inhibitory activity against ALR2; they exhibited IC(50) values in the range of 2.80-45.13 nM. Two compounds with a C7-dimethylcarbamoyl and a C7-diethylcarbamoyl substituent, respectively, were found to be the most active and presented excellent selectivity for ALR2 over aldehyde reductase (ALR1). The structure-activity relationship analyses and molecular modeling studies presented herein highlight the importance of hydrophobic and bulky groups at the C7 position for inhibitory activity and selectivity toward ALR2.

An efficient synthesis of quinoxalinone derivatives as potent inhibitors of aldose reductase.

A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-diones. This new protocol is arguably superior, as it allows the design and preparation of a variety of bioactive quinoxaline-based compounds, which are particularly effective in the treatment of diabetes and its complications. Through this procedure, a new class of quinoxalinone-based aldose reductase inhibitors were synthesized successfully. Most of the inhibitors, with an N1-acetic acid head group and a substituted C3-phenoxy side chain, proved to be potent and selective. Their IC(50) values ranged from 11.4 to 74.8 nM. Among them, 2-(3-(4-bromophenoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid and 2-(6-bromo-3-(4-bromophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid were the most active. Structure-activity relationship and molecular docking studies highlighted the importance of the ether spacer in the C3-phenoxy side chains, and provided clear guidance on the contribution of substitutions both at the core structure and the side chain to activity.

1,2-Benzothiazine 1,1-dioxide carboxylate derivatives as novel potent inhibitors of aldose reductase.

Due to the importance of aldose reductase (ALR2) as a potential drug target in the treatment of diabetic complications, there are increasing interests in design and synthesis of ALR2 inhibitors. Here, we prepared 1,2-benzothiazine 1,1-dioxide acetic acid derivatives and investigated their inhibition activity. Most of these derivatives were found to be active with IC(50) values ranging from 0.11 µM to 10.42 µM, and compound 8d, 2-[2-(4-bromo-2-fluorobenzyl)-1,1-dioxido-2H-1,2-benzothiazin-4(3H)-ylidene]acetic acid, showed the most potent inhibition activity. Further, SAR and docking studies suggest that in comparison with the α,ß-unsaturated derivatives, the saturated carboxylic acid derivatives had a greater binding affinity with the enzyme and thus an enhanced inhibition activity. Therefore, development of more powerful ARIs based on benzothiazine 1,1-dioxide by stereo-controlled synthesis could be expected.

Design and synthesis of potent and selective aldose reductase inhibitors based on pyridylthiadiazine scaffold.

A series of pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against aldose reductase (ALR2). These derivatives were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.038 µM to 11.29 µM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these inhibitors, compound 7d exhibited highest inhibition activity. Structure-activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold.