Exploring of novel oxazolones and imidazolones as anti-inflammatory and analgesic candidates with cyclooxygenase inhibitory action.

Aim: Over the last few decades, therapeutic needs have led to a search for safer COX-2 inhibitors with potential anti-inflammatory and analgesic activity. Materials & methods: A new series of oxazolone and imidazolone derivatives 3a-c and 4a-r were synthesized and evaluated as anti-inflammatory and analgesic agents. COX-1/COX-2 isozyme selectivity testing and molecular docking were performed. Results: All compounds showed good activities comparable to those of the reference, celecoxib. The most active compounds 3a, 4a, 4c, 4e and 4f showed promising gastric tolerability with an ulcer index lower than that of celecoxib. The molecular docking of p-methoxyphenyl derivative 4c showed alkyl interaction with the side pocket His75 of COX-2 and achieved the best anti-inflammatory activity, with a COX-2 selectivity index better than that of celecoxib.

Insight on novel oxindole conjugates adopting different anti-inflammatory investigations and quantitative evaluation.

Background: A dual COX/5-LOX strategy was adopted to develop new oxindole derivatives with superior anti-inflammatory activity. Methods: Three series of oxindoles - esters 4a-p, 6a-l and imines 7a-o - were synthesized and evaluated for their anti-inflammatory and analgesic activities. Molecular docking and predicted pharmacokinetic parameters were done for the most active compounds. A new LC-MS/MS method was developed and validated for the quantification of 4h in rat plasma. Results: Compounds 4h, 6d, 6f, 6j and 7m revealed % edema inhibition up to 100.00%; also, 4l and 7j showed 100.00% writhing protection. Compound 4h showed dual inhibitory activity with IC50 = 0.0533 and 0.4195 µM for COX-2 and 5-LOX, respectively. Molecular docking rationalized the obtained biological activity. The pharmacokinetic parameters of 4h from rat plasma were obtained.

Investigations of new N1-substituted pyrazoles as anti-inflammatory and analgesic agents having COX inhibitory activity.

Background: The search is ongoing for ideal anti-inflammatory and analgesic agents with promising potency and reasonable selectivity. Methods: New N1-substituted pyrazoles with or without an acetamide linkage were synthesized and evaluated for their anti-inflammatory and analgesic activities. COX inhibitory testing, molecular docking, molecular dynamics simulation and antiproliferative activity assessments were performed. Results: All compounds exhibited anti-inflammatory activity up to 90.40% inhibition. They also exhibited good analgesic activity with up to 100% protection. N1-benzensulfonamides 3d, 6c and 6h were preferentially selective agents toward COX-2. Compound 3d showed good cytotoxicity against MCF-7 and HTC116 cancer cell lines. Molecular modeling studies predicted the binding pattern of the most active compounds. Molecular dynamics confirmed the docking results. All compounds showed remarkable pharmacokinetic properties.

Exploring new imines as anti-inflammatory COX and 5-LOX inhibitors with an improved pharmacokinetic profile.

Background: Dual COX/5-LOX inhibition is a bright strategy for developing new potent and safe anti-inflammatory agents. Methods: New imines were synthesized and evaluated for their anti-inflammatory activity. The most active compounds were further investigated for their safety profile. Their molecular docking and physicochemical parameters were assessed. A new LC-MS/MS method was developed for the quantification of compound 4d in rat plasma. Results: Synthesized compounds were found to have anti-inflammatory activity (77-88% edema inhibition). In addition, 4d, 5m and 7d showed analgesic activity (92.50, 95.71 and 96.28% protection, respectively). 4d showed dual COX-2/5-LOX activity. Molecular docking expected the binding pattern of compounds in COX-1, COX-2 and 5-LOX active sites. The in vivo pharmacokinetic parameters of compound 4d were also obtained.

Exploring novel anticancer pyrazole benzenesulfonamides featuring tail approach strategy as carbonic anhydrase inhibitors.

This study aimed to design potent carbonic anhydrase inhibitors (CAIs) based on pyrazole benzenesulfonamide core. Nine series of substituted pyrazole benzenesulfonamide compounds were synthesized with variable groups like sulphamoyl group as in compounds 4a-e, its bioisosteric carboxylic acid as in compounds 5a-e and 8e, ethyl carboxylate ester as in compounds 6a-e and 9a-e, which were designed as potential prodrugs, isothiazole ring as in compound 7, hydrazide derivative 10e, hydroxamic acid derivatives 11a-e and semicarbazide derivatives 12a-c,e. All the synthesized compounds were investigated for their carbonic anhydrase (CA) inhibitory activity against two human CA isoforms hCA IX and hCA XII and compared to acetazolamide (AAZ). Also, the compounds were assessed for their anticancer activity against 60 cancer cell lines according to the US NCI protocol. Compounds 4b, 5b, 5d, 5e, 6b, 9b, 9e and 11b revealed significant inhibitory activity against both isoforms hCA IX and hCA XII, while 6e, 9d, 11d and 11e showed significant inhibitory activity against hCA XII only compared to acetazolamide as a reference. This would highlight these compounds as promising anticancer drugs. Moreover, compound 6e revealed a remarkable cytostatic activity against CNS cancer cell line (SF-539; TGI = 5.58 µM), renal cancer cell line (786-0; TGI = 4.32 µM) and breast cancer cell line (HS 578 T; TGI = 5.43 µM). Accordingly, compound 6e was subjected to cell cycle analysis and apoptotic assay on the abovementioned cell lines at the specified GI50 (0.45, 0.89 and 1.18 µM, respectively). Also, it revealed the increment of total apoptotic cells percentage in 786-0 (53.19%), SF-539 (46.11%) and HS 578 T (43.55%) relative to the control cells (2.07, 2.64 and 2.52%, respectively). In silico prediction of BBB permeability showed that most of the calculations for compound 6e resulted as BBB (+), which is required for a compound targeting CNS. Further, the interaction of the most active compounds with the key amino acids in the active sites of hCA IX and hCA XII was highlighted by molecular docking analysis.

New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation.

New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties.

Development of Isatin-Based Schiff Bases Targeting VEGFR-2 Inhibition: Synthesis, Characterization, Antiproliferative Properties, and QSAR Studies.

Three sets of isatin-based Schiff bases were synthesized utilizing the molecular hybridization approach. Some of the synthesized Schiff bases show significant to moderate antiproliferative properties against MCF7 (breast), HCT116 (colon), and PaCa2 (pancreatic) cancer cell lines with potency compared to reference drugs 5-fluorouracil (5-FU) and Sunitinib. Among all, compound 17 f (3-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)-1-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-methylindolin-2-one) exhibits promising antiproliferative properties against the MCF7 cancer cell line with 2.1-fold more potency than Sunitinib. However, among all the synthesized compounds, three (5-methylisatin derivatives) were the most effective against HCT116 in comparison to 5-FU. Compound 17 f exhibited the highest anti-angiogenic effect on the vasculature as it significantly reduced BV from 43 mm to 2 mm in comparison to 5.7 mm for Sunitinib and flow cytometry supports the arrest of the cell cycle at G1/S phases. In addition, compound 17 f also showed high VEGFR-2 inhibition properties against breast cancer cell lines. Robust 2D-QSAR studies supported the biological data.

Synthesis, molecular modelling and QSAR study of new N-phenylacetamide-2-oxoindole benzensulfonamide conjugates as carbonic anhydrase inhibitors with antiproliferative activity.

In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin N-phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms hCA I, hCA II, hCA IX and hCA XII. The indole-2,3-dione derivative 2h showed the most effective inhibition profile against hCAI and hCA II (KI = 45.10, 5.87 nM) compared to acetazolamide (AAZ) as standard inhibitor. Moreover, 2h showed appreciable inhibition activity against the tumour-associated hCA XII, similar to AAZ showing KI of 7.91 and 5.70 nM, respectively. The analogs 3c and 3d showed good cytotoxicity effects, and 3c revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for 2h and 3c to predict their binding conformations and affinities towards the hCA I, II, IX and XII isoforms.

Design and synthesis of ibuprofen-quinoline conjugates as potential anti-inflammatory and analgesic drug candidates.

A new set of ibuprofen-quinoline conjugates comprising quinolinyl heterocycle and ibuprofen moieties linked by an alkyl chain were synthesized in good yields utilizing an optimized reaction procedure in a molecular hybridization approach to overcome the drawbacks of the current non-steroidal anti-inflammatory drugs. The synthesized conjugates were screened for their anti-inflammatory, and ulcerogenic properties. Several conjugates were found to have significant anti-inflammatory properties in the carrageenan-induced rat paw edema test without showing any ulcerogenic liability. In addition, most conjugates showed promising peripheral analgesic activity in the acetic acid-induced writhing test as well as central analgesic properties in the in vivo hot plate test. The most promising conjugates were the unsubstituted and 6-substituted fluoro- and chloro-derivatives of 2-(trifluoromethyl)quinoline linked to ibuprofen by a propyl chain. Their anti-inflammatory activity was evaluated against LPS-stimulated inflammatory reactions in RAW264.7 mouse macrophages. In this regard, it was found that most of the conjugates were able to significantly reduce the release and production of nitric oxide in the LPS-stimulated macrophages. The secretion and expression of the pro-inflammatory cytokines IL-6, TNF-α, and inducible nitric oxide synthase (iNOS) were also significantly suppressed.

Design and synthesis of novel 4-fluorobenzamide-based derivatives as promising anti-inflammatory and analgesic agents with an enhanced gastric tolerability and COX-inhibitory activity.

Responding to the great demand of developing potent NSAIDs with an enhanced safety profile and reasonable selectivity, in the present study novel 4-fluorobenzamide derivatives were synthesized and screened for their anti-inflammatory and analgesic activities using carrageenan-induced rat paw edema method and acetic acid-induced abdominal writhing in mice, respectively. All the new target compounds except the carbamothioylhydrazine series (5a-d), and the 4-fluorophenyl thiadiazolo derivative 6b showed promising anti-inflammatory activity ranged between 53.43 and 92.36% inhibition of edema (at 3 h) compared to the reference standard indomethacin (65.64%). All the newly synthesized compounds showed potent analgesic activity ranged between 71 and 100 % writhing protection compared to indomethacin (74.06%). Moreover, the most active compounds; the ester hybrids 2a,b, the thioureido quinazolinones 4b,c, and the thiadiazole congener 6a, showed promising gastric tolerability with ulcer index ranged between 0 and 6.60 compared to indomethacin (12.13). The thioureido quinazolinone derivatives 4b,c showed the most potent anti-inflammatory and analgesic activities with a remarkable gastric tolerability compared to the other derivatives. The 4-chlorophenyl derivative 4b is considered the most promising analogue showing 92.36% inhibition of edema, 100% writhing protection in analgesia testing, and a COX-2 selectivity index of 5.75 which was better than that of indomethacin and celecoxib standards (selectivity index = 0.27 and 4.55; respectively). Moreover, it showed an ulcer index equals zero with gastric acidity and mucin levels comparable to that of the control group indicating its minor effect on gastric cell physiology and its high tolerability. Molecular docking studies predicted the binding pattern of the newly synthesized compounds in COX-1 and COX-2 enzymes confirming the ability of the most active candidates to satisfy the structural features required for binding and rationalized their selectivity based on their docking binding patterns and scores. Furthermore, the newly synthesized 4-fluorobenzamide derivatives possess promising predicted pharmacokinetic properties indicated by calculating their key physicochemical parameters and absorption percentages.

Synthesis and computational studies of novel fused pyrimidinones as a promising scaffold with analgesic, anti-inflammatory and COX inhibitory potential.

Addressing the global need for the development of safe and potent NSAIDs, new series of oxadiazolo and thiadiazolo fused pyrmidinones were synthesized and initially tested for their analgesic activity. All tested compounds showed promising analgesic activity compared with the reference standard indomethacin. Moreover, anti-inflammatory activity evaluation, ulcerogenic liability, and in vitro COX-1, COX-2 enzyme inhibition assays were also performed for the most active derivatives. The methoxyphenyl piperazinyl derivative 3d showed analgesic activity surpassing indomethacin with protection of 100%, and 83%; respectively. Also 3d showed good anti-inflammatory activity with relatively lower ulcer index compared with other tested compounds, and potent COX-1 and COX-2 inhibitory activity with IC50 = 0.140, 0.007 µm, respectively, and with a selectivity index of 20.00 which was better than the reference standards and the other tested congeners. Additionally, compounds 3b, 3g and 3h revealed moderate selectivity (SI = 3.53, 3.70 and 5.87, respectively). Moreover, in silico physicochemical parameters revealed that the new fused pyrimidinones demonstrated promising pharmacokinetic properties. Furthermore, computational studies in form of 2D-quantitative structure-activity relationship (2D-QSAR) and 3D-pharmacophore confirmed the potential analgesic properties of the new target compounds.

Synthesis and selective inhibitory effects of some 2-oxindole benzenesulfonamide conjugates on human carbonic anhydrase isoforms CA I, CA II, CA IX and CAXII.

Three series of 2-oxindole benzenesulfonamide conjugates with different linkers were prepared by the condensation reaction of isatin derivatives 1a-e with different benzenesulfonamides. They were screened for their ability to inhibit human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX and hCA XII. Many compounds revealed promising activity and selectivity toward CAI, CAII and CAIX compared to acetazolamide (AAZ) especially compounds 2b (KI = 97.6, 8.0 nM against hCA I, hCA II, respectively) and 3a (KI = 90.2, 6.5 and 21.4 nM against hCA I, hCA II and hCA IX, respectively) relative to AAZ (KI = 250, 12 and 25 nM). Additionally, compound 4a revealed the highest activity against hCA II and hCA IX with KI of 3.0 and 13.9 nM, respectively. Docking of 2b, 3a and 4a into the active site of CA I, II, IX and XII revealed binding mode comparable to AAZ confirming the inhibition results.

Synthesis and molecular docking of new imidazoquinazolinones as analgesic agents and selective COX-2 inhibitors.

AIM: The discovery of new generation of selective COX-2 inhibitors with potential analgesic and anti-inflammatory activity and minimal side effects is a major interest. MATERIALS & METHODS: Novel imidazole and imidazo[1,5-a]quinazoline derivatives were prepared and evaluated for their analgesic and anti-inflammatory activities. COX-1/COX-2 isozyme selectivity testing and molecular docking were performed. Key physicochemical parameters were calculated. RESULTS: All tested compounds exhibited significant activities compared with indomethacin as reference drug. Pharmacological evaluation showed that compounds 3c and 14c possess promising analgesic activity, pronouncing anti-inflammatory effect and reasonable COX-2 selectivity. Molecular docking attributed their good activity to their hydrogen bonding interaction with key amino acids in COX isozymes Arg120, Tyr355 and Ser530. Most compounds obeyed 'Lipinski's rule of five' and possess promising pharmacokinetic properties.

Awareness about autism among school teachers in Oman: a cross-sectional study.

Children with special needs such as those with autism spectrum disorder have been recorded as ostracized and stigmatized in many parts of the world. Little is known about whether such negative views are present among mainstream teachers in Oman. A cross-sectional study was conducted to evaluate school teachers' awareness about autism spectrum disorder in an urban region in Oman. A total of 164 teachers were randomly enrolled from five schools. Misconceptions about autism spectrum disorder were found to be common among mainstream teachers in the country. We posit that such lack of awareness was likely to be rooted with sociocultural patterning as well as conflicting views often "spun" by the scientific community and mass media. Enlightened views toward children with autism spectrum disorder should be presented to Omani teachers to overcome misconceptions and negative attitudes toward children with autism spectrum disorder.

Synthesis of novel 1,3,4-trisubstituted pyrazoles as anti-inflammatory and analgesic agents.

Some novel 1,3,4-trisubstituted pyrazoles were synthesized and screened for their anti-inflammatory and analgesic activities as well as their ulcerogenic liability. They showed anti-inflammatory and analgesic activities with better GIT tolerance than the standard drug phenylbutazone. In addition, IC50 values for 5e and 8e were recorded. Compound 5e was found to be the most active one as anti-inflammatory and analgesic agent. On the other hand, COX-1/COX-2 isozyme selectivity was also done which showed equal inhibition to both isoforms.

Levels of heavy metals and essential minerals in hair samples of children with autism in Oman: a case-control study.

Toxic levels of heavy metals and low levels of essential minerals have been suggested to play a critical role in the pathogenesis of autism spectrum disorders (ASD). This study documents the levels of heavy metals and essential minerals in hair samples of children with ASD in Muscat, the urbanized capital of Oman, Muscat. The study included 27 children with ASD and 27 matched non-ASD controls. Parental interviews were held and dietary intake questionnaires completed in conjunction with the collection of hair samples. Analysis of heavy metals and essential minerals was carried out by inductively coupled plasma mass spectrometry. Chi-square analysis and non-parametric Fisher's exact tests were used to assess statistical significance. Children with ASD had significantly higher levels of all 11 analyzed heavy metals in their hair samples (P < 0.05), ranging from 150 to 365 % of control levels. ASD children also had significantly higher levels of essential minerals sulfur, sodium, magnesium, potassium, zinc, and iron, but lower levels of calcium and copper in their hair samples. This study corroborates data from previous studies in different parts of the world indicating the presence of elevated levels of heavy metals and selective depletion of essential minerals in the hair of children with ASD.