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Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors. Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.

A series of 2-(4-substitutedmethylphenyl)propionic acid derivatives (6a–6m) were synthesized, characterized and evaluated for cyclooxygenase (COX) enzyme inhibitory and antimicrobial activity. Test compounds that exhibited good COX inhibition and antibacterial activity were further screened for their cytotoxicity and genotoxicity. Compounds 6h and 6l showed better COX-1 and COX-2 inhibition when compared to ibuprofen. Inhibition potency of these compounds against COX-2 was very close to that of nimesulide. The compounds 6d, 6h, 6l and 6m displayed promising antibacterial property when compared to chloramphenicol. However, the compound 6l was emerged as the best dual COX inhibitory-antibacterial agent in this study. The ADME prediction of the compounds revealed that they may have a good pharmacokinetic profile. Docking results of the compounds 6h and 6l with COX-1 (PDB ID: 1EQG) also exhibited a strong binding profile.

Chronic inflammation is implicated in the development of various multifactorial diseases, including cancer, diabetes, arthritis, cardiovascular disorders, Alzheimer's disease, and autoimmune diseases. The enzymes that play a key role in the onset of the inflammation are cyclooxygenases (COXs) and lipoxygenases (LOXs). In recent years, cinnamic acid hybrid molecules, particularly those incorporating a nitric oxide (NO) donor moiety, have attracted considerable attention as potential pharmacological agents for the treatment of multifactorial diseases. In the present study, novel cinnamic acid-nitric oxide (NO) donor hybrids were synthesized as multitarget agents and evaluated for their antioxidant, anti-inflammatory, and cytotoxic properties. In particular, hybrids - , - , - , and were synthesized and evaluated as lipid peroxidation and LOX inhibitors, while selected molecules were further tested as COX-1 and COX-2 inhibitors. Hybrids - , - , and that contain a NO donor moiety, were additionally tested as albumin denaturation inhibitors and for their ability to release NO. The results indicated that compound is a promising multitarget agent, exhibiting the lowest IC for LOX inhibition, significant antioxidant activity, and the highest NO donor potency. Furthermore, compound demonstrated significant inhibitory activity against both COX-2 and LOX, suggesting its potential as a dual COX-LOX inhibitor. Additionally, compound exhibited the strongest cytotoxic activity among the tested compounds, with EC values ranging from 36 to 45 μM across multiple cancer cell lines. All synthesized compounds were also evaluated through in silico studies.

Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly available, they are sometimes insufficient and can cause dangerous adverse effects. As yet reported, derivatives of pyrrolo[3,4-d]pyridazinone are potent COX-2 inhibitors with a COX-2/COX-1 selectivity index better than meloxicam. Considering that N-acylhydrazone (NAH) moiety is a privileged structure occurring in many promising drug candidates, we decided to introduce this pharmacophore into new series of pyrrolo[3,4-d]pyridazinone derivatives. The current paper presents the synthesis and in vitro, spectroscopic, and in silico studies evaluating the biological and physicochemical properties of NAH derivatives of pyrrolo[3,4-d]pyridazinone. Novel compounds 5a-c–7a-c were received with high purity and good yields and did not show cytotoxicity in the MTT assay. Their COX-1, COX-2, and 15-LOX inhibitory activities were estimated using enzymatic tests and molecular docking studies. The title N-acylhydrazones appeared to be promising dual COX/LOX inhibitors. Moreover, spectroscopic and computational methods revealed that new compounds form stable complexes with the most abundant plasma proteins–AAG and HSA, but do not destabilize their secondary structure. Additionally, predicted pharmacokinetic and drug-likeness properties of investigated molecules suggest their potentially good membrane permeability and satisfactory bioavailability.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit frequent and sometimes severe adverse effects, including gastrointestinal ulcerations and cardiovascular disorders. In an effort to obtain safer NSAIDs, we assessed the direct cyclooxygenase (COX) inhibition activity and we investigated the potential COX binding mode of some previously reported 2-(trimethoxyphenyl)-thiazoles. The in vitro COX inhibition assays were performed against ovine COX-1 and human recombinant COX-2. Molecular docking studies were performed to explain the possible interactions between the inhibitors and both COX isoforms binding pockets. Four of the tested compounds proved to be good inhibitors of both COX isoforms, but only compound A3 showed a good COX-2 selectivity index, similar to meloxicam. The plausible binding mode of compound A3 revealed hydrogen bond interactions with binding site key residues including Arg120, Tyr355, Ser530, Met522 and Trp387, whereas hydrophobic contacts were detected with Leu352, Val349, Leu359, Phe518, Gly526, and Ala527. Computationally predicted pharmacokinetic profile revealed A3 as lead candidate. The present data prove that the investigated compounds inhibit COX and thus confirm the previously reported in vivo anti-inflammatory screening results suggesting that A3 is a suitable candidate for further development as a NSAID.

In trying to develop new anticancer agents, a series of sulfonylhydrazones were synthesized. All synthesized compounds were checked for identity and purity using elemental analysis, TLC and HPLC and were characterized by their melting points, FT-IR and NMR spectral data. All synthesized compounds were evaluated for their cytotoxic activity against prostate cancer (PC3), breast cancer (MCF-7) and L929 mouse fibroblast cell lines. Among them, N′-[(2-chloro-3-methoxyphenyl)methylidene]-4-methylbenzenesulfonohydrazide (3k) showed the most potent anticancer activity against both cancer cells with good selectivity (IC50 = 1.38 μM on PC3 with SI = 432.30 and IC50 = 46.09 μM on MCF-7 with SI = 12.94). Further investigation confirmed that 3k displayed morphological alterations in PC3 and MCF-7 cells and promoted apoptosis through down-regulation of the Bcl-2 and upregulation of Bax expression. Additionally, compound 3k was identified as the most potent COX-2 inhibitor (91% inhibition) beside lower COX-1 inhibition. Molecular docking of the tested compounds represented important binding modes which may be responsible for their anticancer activity via inhibition of the COX-2 enzyme. Overall, the lead compound 3k deserves further development as a potential anticancer agent.Graphic abstractSulfonylhydrazones was synthesized and N′-[(2-chloro-3-methoxyphenyl)methylidene]-4- methylbenzenesulfonohydrazide (3k) was identified as the most potent anticancer agent and COX-2 inhibitor. In addition, this compound docked inside the active site of COX-2 succesfully.

In the present paper, we describe the biological activity of the newly designed and synthesized series N-substituted 3,4-pyrroledicarboximides 2a–2p. The compounds 2a–2p were obtained in good yields by one-pot, three-component condensation of pyrrolo[3,4-c]pyrrole scaffold (1a–c) with secondary amines and an excess of formaldehyde solution in C2H5OH. The structural properties of the compounds were characterized by 1H NMR, 13C NMR FT-IR, MS, and elemental analysis. Moreover, single crystal X-ray diffraction has been recorded for compound 2h. The colorimetric inhibitor screening assay was used to obtain their potencies to inhibit COX-1 and COX-2 enzymes. According to the results, all of the tested compounds inhibited the activity of COX-1 and COX-2. Theoretical modeling was also applied to describe the binding properties of compounds towards COX-1 and COX-2 cyclooxygenase isoform. The data were supported by QSAR study.

Numerous medications, including non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, are available to treat inflammation. However, due to their side effects, the search for new anti-inflammatory drugs remains a major research focus. The current study addresses the synthesis, characterization of sulphonyl hydrazide, followed by in vitro and in silico analyses. Sulphonyl hydrazide compounds (R1–R5) were synthesized and characterized using physicochemical and spectroscopic methods, followed by anti-inflammatory evaluation and in silico approaches. The COX-2 and 5-LOX pathways were used for anti-inflammatory potential of compounds. The test compounds (R1–R5) showed significant activity ( P  < 0.05) against various in vitro enzymes. The compound R3 exhibited remarkable potency in inhibiting both COX-2 and 5-LOX, at various concentrations with IC 50 values of 0.84 µM and 0.46 µM, respectively. The compounds were also evaluated for their in vitro cytotoxicity in theHek293 cell line using the MTT assay to study. The synthesized compounds were further explored for in vivo anti-inflammatory potential, followed by an acute toxicity study. The compound R3 led to decreased paw edema from the 1st to 5th hour after carrageenan injection. All other compounds also showed reasonable to moderate anti-inflammatory potential. To address the compounds’ mechanisms of action, they were evaluated against various phlogistic mediators, including histamine, bradykinin, leukotrienes, and prostaglandins, to confirm the anti-inflammatory pathway of the most potent synthesized compound. Their binding strategies were identified using molecular docking assays, which involved examining the interaction between the compounds and the amino acid residues in the binding pockets of the enzymes. Again, compound R3 showedstrong binding affinity with the targeted receptors. The findings demonstrated that synthesized sulphonyl hydrazide complexes have significant efficacy in mitigating inflammation. Taken together, the new sulphonyl hydrazide compounds (R1–R5) elicited potential COX-2 and 5-LOX inhibition in vitro that was markedly augmented by molecular docking.

C- glycosides are important class of molecules exhibit diverse biological activities and present as structural motif in many natural products. Two series of new pyrazoline and isoxazole bridged indole C -glycoside molecular hybrids (n = 36) were efficiently synthesized starting from diverse indole 3-carboxaldehydes derived α, β-unsaturated ketone derivatives of β-D-glucosyl-propan-2-one, β-D-galactosyl-propan-2-one and β-D-mannosyl-propan-2-one, reacting with hydrazine hydrate and hydroxyl amine hydrochloride in shorter reaction time (15 min) under microwave assisted condition. Anticancer activity of these newly synthesized pyrazoline and isoxazole bridged indoles C -glycoside hybrids were determined in details through cellular assays against MCF-7, MDA-MB-453 and MDA-MB-231 cancer cell lines. The selected library members displayed low micromolar (IC 50  = 0.67–4.67 µM) and selective toxicity against breast cancer cell line (MCF-7). Whereas these compounds were nontoxic towards normal cell line (MCF-10A). Mechanistic studies showed that, active compounds inhibit COX-2 enzyme, which was also supported by molecular docking studies. These findings are expected to provide new leads towards anticancer drug discovery.

Cyclic imides containing 3-benzenesulfonamide, oxime, and β-phenylalanine derivatives were synthesised and evaluated to elucidate their in vivo anti-inflammatory and ulcerogenic activity and in vitro cytotoxic effects. Most active anti-inflammatory agents were subjected to in vitro COX-1/2 inhibition assay. 3-Benzenesulfonamides (2-4, and 9), oximes (11-13), and β-phenylalanine derivative (18) showed potential anti-inflammatory activities with 71.2-82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides 4, 9, 12, 13, and 18 possessed ED 50 of 35.4-45.3 mg kg −1 relative to that of celecoxib (34.1 mg kg −1 ). For the cytotoxic evaluation, the selected derivatives 2-6 and 8 exhibited weak positive cytotoxic effects (PCE = 2/59-5/59) at 10 μM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide (2-5, and 9), acetophenone oxime (11-14, 18, and 19) exhibited high selectivity against COX-2 with SI > 55.6-333.3 relative to that for celecoxib [SI > 387.6]. β-Phenylalanine derivatives 21-24 and 28 were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46-0.68.