Barbiturate-sulfonate hybrids as potent cholinesterase inhibitors: design, synthesis and molecular modeling studies.

Aim: Design and synthesis of a series of 5-benzylidene(thio)barbiturates 3a-r. Methodology: Evaluation of the inhibitory activity of the new chemical entities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Donepezil as the standard reference. Results & Conclusion: Compound 3r emerged as the most potent AChE inhibitor (IC50 = 9.12 µM), while compound 3q exhibited the highest inhibitory activity against BChE (IC50 = 19.43 µM). Toxicological bioassays confirmed the absence of cytotoxicity for the most potent compounds at the tested doses. Molecular docking analysis demonstrated that the tested derivatives effectively bind to the active sites of both enzymes. Overall, this study sheds light on the potential of barbiturate-sulfonate conjugates as promising drug candidates.

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Design, synthesis, molecular docking and biological evaluation of 1,3,5-trisubstituted-1H-pyrazole derivatives as anticancer agents with cell cycle arrest, ERK and RIPK3- kinase activities.

The need for new ERK and RIPK3 kinase modulators arises from their central roles in cellular processes, especially in diseases like cancer. This research focused on a ligand-based strategy, incorporating previously documented 1,3,5-trisubstituted-1H-pyrazole derivatives, to craft innovative inhibitors specifically targeting ERK and RIPK3 kinases. Compounds 6, 7, 10a, 10c, and 10d exhibited significant cytotoxicity against PC-3 and MCF-7 cancer cell lines, with IC50 values ranging from 21.9 to 28.6 µM and 3.90-35.5 µM, respectively values surpassing those of the reference compound Doxorubicin. Additionally, cell cycle analysis revealed intriguing results, particularly with 10d inducing cell cycle arrest at the S phase in treated PC-3 cells, indicating potential DNA replication phase inhibition. Moreover, compounds 6, 10a, and 10d exhibited promising results in the in vitro kinase assay supported by molecular docking studies. The core scaffold of these compounds established interactions with vital amino acids within the active pockets of ERK and RIPK3 kinases, thereby securely anchoring them in place. These findings underscore the development of promising modulators for ERK and RIPK3 kinases, suggesting their potential for future contributions to cancer treatments.

Hydrazone-sulfonate hybrids as potential cholinesterase inhibitors: design, synthesis and molecular modeling simulation.

Aim: Design and synthesis of a series of hydrazone-sulfonate hybrids, 5a-r. Methodology: The inhibitory properties of the synthesized compounds against acetylcholinesterase and butyrylcholinesterase were evaluated using donepezil as the reference standard. Results & conclusion: Compound 5e was identified as the most potent inhibitor of acetylcholinesterase (IC50 = 9.30 µM), and compound 5i was the most potent inhibitor of butyrylcholinesterase (IC50 = 11.82 µM). To confirm the safety of the most potent hits at the used doses, toxicological bioassays were conducted. Molecular docking was performed and the tested derivatives were found to fit well in the active sites of both enzymes. This study provides valuable insights into the potential of hydrazone-sulfonate hybrids as drug candidates.

Therapeutic potential of 1,3,4-oxadiazoles as potential lead compounds for the treatment of Alzheimer's disease.

Monoamine oxidase and cholinesterase enzymes are important targets for the treatment of several neurological diseases especially depression, Parkinson disease and Alzheimer's. Here, we report the synthesis and testing of new 1,3,4-oxadiazole derivatives as novel inhibitors of monoamine oxidase enzymes (MAO-A and MAO-B) and cholinesterase enzymes (acetyl and butyryl cholinesterase (AChE, BChE). Compounds 4c, 4d, 4e, 4g, 4j, 4k, 4m, 4n displayed promising inhibitory effects on MAO-A (IC50: 0.11-3.46 µM), MAO-B (IC50: 0.80-3.08 µM) and AChE (IC50: 0.83-2.67 µM). Interestingly, compounds 4d, 4e and 4g are multitargeting MAO-A/B and AChE inhibitors. Also, Compound 4m displayed promising MAO-A inhibition with IC50 of 0.11 µM and high selectivity (∼25-fold) over MAO-B and AChE enzymes. These newly synthesized analogues represent promising hits for the development of promising lead compounds for neurological disease treatment.

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.

Preliminary Evidence of the Potent and Selective Adenosine A2B Receptor Antagonist PSB-603 in Reducing Obesity and Some of Its Associated Metabolic Disorders in Mice.

The adenosine A2A and A2B receptors are promising therapeutic targets in the treatment of obesity and diabetes since the agonists and antagonists of these receptors have the potential to positively affect metabolic disorders. The present study investigated the link between body weight reduction, glucose homeostasis, and anti-inflammatory activity induced by a highly potent and specific adenosine A2B receptor antagonist, compound PSB-603. Mice were fed a high-fat diet for 14 weeks, and after 12 weeks, they were treated for 14 days intraperitoneally with the test compound. The A1/A2A/A2B receptor antagonist theophylline was used as a reference. Following two weeks of treatment, different biochemical parameters were determined, including total cholesterol, triglycerides, glucose, TNF-α, and IL-6 blood levels, as well as glucose and insulin tolerance. To avoid false positive results, mouse locomotor and spontaneous activities were assessed. Both theophylline and PSB-603 significantly reduced body weight in obese mice. Both compounds had no effects on glucose levels in the obese state; however, PSB-603, contrary to theophylline, significantly reduced triglycerides and total cholesterol blood levels. Thus, our observations showed that selective A2B adenosine receptor blockade has a more favourable effect on the lipid profile than nonselective inhibition.

Bis-pharmacophore of cinnamaldehyde-clubbed thiosemicarbazones as potent carbonic anhydrase-II inhibitors.

Here, we report the synthesis, carbonic anhydrase-II (CA-II) inhibition and structure-activity relationship studies of cinnamaldehyde-clubbed thiosemicarbazones derivatives. The derivatives showed potent activities in the range of 10.3 ± 0.62-46.6 ± 0.62 µM. Among all the synthesized derivatives, compound 3n (IC50 = 10.3 ± 0.62 µM), 3g (IC50 = 12.1 ± 1.01 µM), and 3h (IC50 = 13.4 ± 0.52 µM) showed higher inhibitory activity as compared to the standard inhibitor, acetazolamide. Furthermore, molecular docking of all the active compounds was carried out to predict their behavior of molecular binding. The docking results indicate that the most active hit (3n) specifically mediate ionic interaction with the Zn ion in the active site of CA-II. Furthermore, the The199 and Thr200 support the binding of thiosemicarbazide moiety of 3n, while Gln 92 supports the interactions of all the compounds by hydrogen bonding. In addition to Gln92, few other residues including Asn62, Asn67, The199, and Thr200 play important role in the stabilization of these molecules in the active site by specifically providing H-bonds to the thiosemicarbazide moiety of compounds. The docking score of active hits are found in range of - 6.75 to - 4.42 kcal/mol, which indicates that the computational prediction correlates well with the in vitro results.

Irreversible Antagonists for the Adenosine A2B Receptor.

Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for the immunotherapy of cancer. In the present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding was confirmed in radioligand binding and bioluminescence resonance energy transfer(BRET)-based Gα15 protein activation assays by performing ligand wash-out and kinetic experiments. p-(1-Propylxanthin-8-yl)benzene sulfonyl fluoride (6a, PSB-21500) was the most potent and selective irreversible A2BAR antagonist of the present series with an apparent Ki value of 10.6 nM at the human A2BAR and >38-fold selectivity versus the other AR subtypes. The corresponding 3-cyclopropyl-substituted xanthine derivative 6c (PSB-21502) was similarly potent, but was non-selective versus A1- and A2AARs. Attachment of a reactive sulfonyl fluoride group to an elongated xanthine 8-substituent (12, Ki 7.37 nM) resulted in a potent, selective, reversibly binding antagonist. Based on previous docking studies, the lysine residue K2697.32 was proposed to react with the covalent antagonists. However, the mutant K269L behaved similarly to the wildtype A2BAR, indicating that 6a and related irreversible A2BAR antagonists do not interact with K2697.32. The new irreversible A2BAR antagonists will be useful tools and have the potential to be further developed as therapeutic drugs.

A2B Adenosine Receptor Antagonists with Picomolar Potency.

The A2B adenosine receptor (A2BAR) was proposed as a novel target for the (immuno)therapy of cancer since A2BAR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the A2BAR combined with high selectivity. Functional groups were introduced, which will allow the attachment of dyes and other reporter groups. 8-(4-((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A2B-antagonist ( Ki 0.0835 nM, KB 0.0598 nM, human A2BAR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A2BAR, making it a promising tool for preclinical studies. Computational studies predicted halogen bonding to contribute to the outstanding potency of 34.

Part I. Synthesis, biological evaluation and docking studies of new 2-furylbenzimidazoles as antiangiogenic agents.

2-(2-Furyl)-1H-benzimidazoles 3-11 were synthesized and tested for their in vitro VEGF inhibition in MCF-7 cancer cell line. Compound 5a was more potent than Tamoxifen, and compounds 3b, 5a, 5c, 6b, 7a and 10 showed promising potency. Furthermore, compounds (6b, 7a and 10) showed remarkable selective inhibition of COX-2 enzyme close to that of Celecoxcib. Additionally, docking studies were performed using AutoDock 4.2 into the VEGFR2 kinase. Significant correlation exists between the biological activity (IC50 and %VEGF inhibition) against MCF-7 cell line and the molecular docking results (Ki and ΔGb) with correlation coefficients (R(2)) of 0.5513 and 0.4623 respectively. Accordingly, most of the synthesized 2-(2-furyl)-1H-benzimidazoles showed strong antiangiogenic activity against VEGFR2 kinase.

Synthesis, biological evaluation, and docking studies of new 2-furylbenzimidazoles as anti-angiogenic agents: part II.

The 2-(5-methyl-2-furyl)-1H-benzimidazole moiety has shown promising activity against vascular endothelial growth factor (VEGF)-induced angiogenesis. In part I of this study, we have synthesized new analogs and tested their anti-angiogenic potentials. Here, we continue our previous study with different new analogs. Some compounds show promising cytotoxic activity against the human breast cancer cell line MCF-7, with IC50 in the range of 7.80-13.90 µg/mL, and exhibited remarkable in vitro inhibition against VEGF in the MCF-7 cancer cell line, with 95-98% of inhibition in comparison to tamoxifen as reference (IC50: 8.00 µg/mL, % of inhibition = 98%). Additionally, a molecular docking study was carried out to gain insight into plausible binding modes and to understand the structure-activity relationships of the synthesized compounds.

Rational drug design for identifying novel multi-target inhibitors for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the hard-treating and high mortality cancers for which novel therapies are very much in need. Sorafenib is the first medication that is now approved for the treatment of patients with advanced HCC [1]. Sorafenib is a multikinase inhibitor targeting the Raf serine/ threonine kinases and the VEGFR1-3, PDGFR-b, c-Kit, Flt3 and p38 tyrosine kinases [1]. Here, an in silico approach was directed to identify novel multi-kinase inhibitors as potential candidate therapies for HCC. The Molecular Operating Environment (MOE) was used for docking studies, pharmacophore building and virtual screening of chemical molecules databases. The docking/scoring methods of MOE were validated by reproducing the docking interactions and poses of Sorafenib with smallest root mean square deviations. The three receptors for which multi-targeting compounds were screened for were: B-Raf, p38 and VEGFR-2 tyrosine kinases. After identifying the main binding sites of the target receptors, we started our studies by the docking of Sorafenib in comparison to tyrosine kinase inhibitors collected from the literature. A pharmacophore based on the SAR of Sorafenib was built using flexible alignment methods. Next, pharmacophore based virtual screening on four chemical molecules databases; Open NCI Database [2], Zinc [3], Maybridge [4] and drug bank [5] was done resulting in 2928 hit compounds that were subsequently subjected to filtration according to their binding free energies, interactions exhibited with the receptors, in silico ADMET properties and Lipinski's rule of five for molecule drugability [6]. Finally 7 compounds were selected as they exhibited excellent binding interactions with the receptors in addition to their high safety profile that are recommended for further development.