Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation.

The eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC50) values of 2.7-63 µM. The tests confirmed that 5b and 5d were potent JNK-2 inhibitors, with IC50 of 2.0 and 0.9 µM, respectively, whereas 6 h selectively inhibited EGFR protein kinase (EGFR-PK) (IC50 = 1.7 µM). Notably, 6c inhibited both kinases, with IC50 values of 2.7 and 3.0 µM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce apoptosis and induce cell cycle arrest at different cell phases.

Studies on the Nonalkaloidal Secondary Metabolites of Hippeastrum vittatum (L'Her.) Herb. Bulbs.

Sixteen chemically varied metabolites were isolated from the bulbs of Hippeastrum vittatum (L'Her.) Herb., including eight flavonoids [3'-methyl isoliquiritigenin (2), 7-hydroxyflavan (8), 7-hydroxyflavanone (9), 7-hydroxyflavan-3-ol (10), 7-methoxy-3',4'-methylenedioxyflavan-3-ol (11), 7-hydroxy-3',4'-methylenedioxy flavan (12), 2',4'-dihydroxy-3'-methyl-3,4-methylenedioxychalcone (13), and isoliquiritigenin (14)], four acetophenones [2,6-dimethoxy-4-hydroxyacetophenone (3), 2,4-dihydroxyacetophenone (4), 2,4-dihydroxy-6-methoxy-3-methylacetophenone (6), and 2,4,6-trimethoxyacetophenone (7)], two alkaloids [lycorine (1) and narciprimine (15)], one phenol derivative [p-nitrophenol (5)], and one steroid [ß-sitosterol 3-O-ß-glucopyranoside (16)]. Their structures were elucidated by combining one- and two-dimensional NMR and ESI-MS techniques and by comparison with the reported literature data and some authentic samples. Except for lycorine (1), the isolated metabolites were obtained herein for the first time from Hippeastrum plants, among which compound 13 was identified as a new chalcone derivative. Additionally, the total phenolic and flavonoid contents of the total ethanol extract and different fractions of the bulbs were determined by the Folin-Ciocalteu and aluminum chloride colorimetric methods, respectively, whereas their antioxidant potential was compared using the phosphomolybdenum and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assays. Finally, the binding affinities of compounds 1-16 to some key target proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), namely, main protease (Mpro), papain-like protease (PLpro), and RNA-dependent RNA polymerase (RdRp), were screened and compared using molecular docking analysis. The possible chemotaxonomic significance of the identified metabolites was also discussed.

Exploration of the Safety and Solubilization, Dissolution, Analgesic Effects of Common Basic Excipients on the NSAID Drug Ketoprofen.

Since its introduction to the market in the 1970s, ketoprofen has been widely used due to its high efficacy in moderate pain management. However, its poor solubility and ulcer side effects have diminished its popularity. This study prepared forms of ketoprofen modified with three basic excipients: tris, L-lysine, and L-arginine, and investigated their ability to improve water solubility and reduce ulcerogenic potential. The complexation/salt formation of ketoprofen and the basic excipients was prepared using physical mixing and coprecipitation methods. The prepared mixtures were studied for solubility, docking, dissolution, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), in vivo evaluation for efficacy (the writhing test), and safety (ulcerogenic liability). Phase solubility diagrams were constructed, and a linear solubility (AL type) curve was obtained with tris. Docking studies suggested a possible salt formation with L-arginine using Hirshfeld surface analysis. The order of enhancement of solubility and dissolution rates was as follows: L-arginine > L-lysine > tris. In vivo analgesic evaluation indicated a significant enhancement of the onset of action of analgesic activities for the three basic excipients. However, safety and gastric protection indicated that both ketoprofen arginine and ketoprofen lysine salts were more favorable than ketoprofen tris.

Vanillin-Based Indolin-2-one Derivative Bearing a Pyridyl Moiety as a Promising Anti-Breast Cancer Agent via Anti-Estrogenic Activity.

The structure-based design introduced indoles as an essential motif in designing new selective estrogen receptor modulators employed for treating breast cancer. Therefore, here, a series of synthesized vanillin-substituted indolin-2-ones were screened against the NCI-60 cancer cell panel followed by in vivo, in vitro, and in silico studies. Physicochemical parameters were evaluated with HPLC and SwissADME tools. The compounds demonstrated promising anti-cancer activity for the MCF-7 breast cancer cell line (GI = 6-63%). The compound with the highest activity (6j) was selective for the MCF-7 breast cancer cell line (IC50 = 17.01 µM) with no effect on the MCF-12A normal breast cell line supported by real-time cell analysis. A morphological examination of the used cell lines confirmed a cytostatic effect of compound 6j. It inhibited both in vivo and in vitro estrogenic activity, triggering a 38% reduction in uterine weight induced by estrogen in an immature rat model and hindering 62% of ER-α receptors in in vitro settings. In silico molecular docking and molecular dynamics simulation studies supported the stability of the ER-α and compound 6j protein-ligand complex. Herein, we report that indolin-2-one derivative 6j is a promising lead compound for further pharmaceutical formulations as a potential anti-breast cancer drug.

Discovery of oxindole-based FLT3 inhibitors as a promising therapeutic lead for acute myeloid leukemia carrying the oncogenic ITD mutation.

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the design of new FLT3 inhibitors as potential hits for AML irradiation. Cell-based screening was performed with 18 oxindole derivatives and 5a-c inhibited 68%-73% and 83%-91% of internal tandem duplication (ITD)-mutated MV4-11 cell growth for 48- and 72-h treatments while only 0%-2% and 27%-39% in wild-type THP-1 cells. The most potent compound 5a inhibited MV4-11 cells with IC50 of 4.3 µM at 72 h while it was 8.7 µM in THP-1 cells, thus showing two-fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High-throughput protein profiling revealed low levels of the growth factors IGFBP-2 and -4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF-ß. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC50 values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.

Design, Preparation and Evaluation of Supramolecular Complexes with Curcumin for Enhanced Cytotoxicity in Breast Cancer Cell Lines.

Curcumin is one of the most researched phytochemicals by pharmacologists and formulation scientists to unleash its potential therapeutic benefits and tackle inherent biopharmaceutic problems. In this study, the native ß-cyclodextrin (CD) and three derivatives, namely, Captisol (sulfobutyl ether ß-CD), hydroxypropyl ß-cyclodextrin, and hydroxyethyl ß-cyclodextrin were investigated for inclusion complexes with curcumin using two preparation methods (physical mixing and solvent evaporation). The prepared complexes were studied for docking, solubility, FTIR, DSC, XRD, and dissolution rates. The best-fitting curcumin: cyclodextrins (the latter of the two CDs) were evaluated for cytotoxicity using human breast cell lines (MCF-7). Dose-dependent cytotoxicity was recorded as IC50% for curcumin, curcumin: hydroxyethyl ß-cyclodextrin, and curcumin: hydroxypropyl ß-cyclodextrin were 7.33, 7.28, and 19.05 µg/mL, respectively. These research findings indicate a protective role for the curcumin: hydroxypropyl ß-cyclodextrin complex on the direct cell lines of MCF-7.

Controlled microwave-assisted reactions: A facile synthesis of polyfunctionally substituted phthalazines as dual EGFR and PI3K inhibitors in CNS SNB-75 cell line.

Brain tumors are stubborn cancers with poor prognosis and disappointing survival rates. Targeted cancer therapeutics with higher efficacy and lower resistance are highly demanded. An efficient one-pot synthesis of polyfunctionalized phthalazines derivatives was developed by reacting ethyl 1-aryl-5-cyano-1,6-dihydro-4-methyl-6-oxo-3-pyridazine-carboxylates with cinnamonitrile derivatives and the cycloaddition reaction of thieno[3,4-d]pyridazines with activated double or triple bond systems under controlled microwave heating with high yields. The resultant synthesized phthalazines (5a-e, 9 and 13) were tested for their in vitro anti-cancer activities by using in vitro one dose assay at National Cancer institute, USA. Only phthalazine (5b) showed broad spectrum anti-tumor activity against most tested cancer cell lines from all subpanels with mean % GI = 22.61. Interestingly, all tested compounds showed varying growth inhibitory activity against a particular cell line, CNS SNB-75 cell line, but (5b) exhibited the highest growth inhibitory activity against CNS-SNB-75 cell line with (GI% = 108.81) and (IC50 = 3.703 ± 0.2) compared to erlotinib; (IC50 = 12.5 ± 0.68). It caused Pre-G1 apoptosis and growth arrest at S phase. It also increased percentage of the total apoptotic cells in CNS-SNB-75 cell line (39.26%) compared to control cells (2.17%) in the annexin V-FITC experiment. It revealed pronounced EGFR inhibitory activity (IC50 = 47.27 ± 2.41 ng/mL) compared to erlotinib (IC50 = 30.7 ± 1.56 ng/mL). It also inhibited the different PI3K isoforms α, ß, γ and δ (with IC50 of 4.39, 13.6, 12.5 and 3.11 µg/mL, respectively compared to LY294002 (with IC50 of 12.7, 8.57, 6.89 and 5.7 µg/mL, respectively). It also caused significant lower protein expression levels of pPI3K, AKT, pAKT and Bcl2 and higher protein expression levels of BAX, Casp3 and Casp9 when compared to untreated cells. Conclusion: Phthalazine (5b) may be an effective, convenient and safe anti-cancer agent acting via proapoptotic and dual EGFR and PI3K kinase inhibitory actions in CNS SNB-75 cell line.

Thiazolidine-2,4-dione-linked ciprofloxacin derivatives with broad-spectrum antibacterial, MRSA and topoisomerase inhibitory activities.

A series of ciprofloxacin/thiazolidine-2,4-dione hybrids 3a-m were prepared and identified by IR, 1HNMR, 13CNMR and elemental analysis. The antibacterial activity results of the designed hybrids revealed a shift of spectrum toward Gram-positive bacteria. They exhibited excellent activity against S. aureus ATCC 6538, with the most potent compounds being 3a, 3e, 3g, 3i, 3k, 3l and 3m possessing MICs of 0.02, 2.03, 0.64, 0.35, 1.04, 0.22 and 0.36 µM, respectively, compared to their parent compound ciprofloxacin (MIC: 5.49 µM). They also showed interesting activity against MRSA AUMC 261 with 3a, 3e and 3l showing MIC values of 5 nM. Reduced activity was observed against Gram-negative bacteria with compound 3l exhibiting a slightly higher activity against K. pneumoniae ATCC10031 with a MIC value of 0. 08 µM. Mechanistically, the incorporation of thiazolidine-2,4-dione ring into ciprofloxacin retained its ability to inhibit DNA synthesis via inhibiting both topoisomerase IV and DNA gyrase of S. aureus. Compounds 3a, 3l and 3m were more potent than ciprofloxacin for topoisomerase IV (IC50 = 0.3-1.9 µM) and gyrase (IC50 = 0.22-0.31 µM) inhibition, which coincide with their antibacterial activity against S. aureus ATCC 6538. Docking against DNA gyrase active site confirmed the ability of the tested compounds to form stable complexes with the enzyme; like that of ciprofloxacin, 3a, 3i, 3k, 3m and 3l reconsidered promising broad-spectrum antibacterial agents targeting topoisomerase IV and gyrase enzymes and have good activity against MRSA.

A Novel Curcumin Arginine Salt: A Solution for Poor Solubility and Potential Anticancer Activities.

Curcumin is a natural polyphenolic compound with well-known anticancer properties. Poor solubility and permeability hamper its use as an anticancer pharmaceutical product. In this study, L-arginine, a basic amino acid and a small hydrophilic molecule, was utilized to form a salt with the weak acid curcumin to enhance its solubility and potentiate the anticancer activities of curcumin. Two methods were adopted for the preparation of curcumin: L-arginine salt, namely, physical mixing and coprecipitation. The ion pair or salt was characterized for docking, solubility, DSC, FTIR, XRD, in vitro dissolution, and anticancer activities using MCF7 cell lines. The molecular docking suggested a salt/ion-pair complex between curcumin and L-arginine. Curcumin solubility was increased 335- and 440-fold by curcumin in L-arginine, physical, and co-precipitated mixtures, respectively. Thermal and spectral analyses supported the molecular docking and formation of a salt/ion pair between curcumin and L-arginine. The cytotoxicity of curcumin L-arginine salt significantly improved (p < 0.05) by 1.4-fold, as evidenced by the calculated IC50%, which was comparable to Taxol (the standard anticancer drug but with common side effects).

New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors.

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 µM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 µM. A mechanistic study demonstrated 4b's efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 µM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 µg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 µg/mL and 0.40 µg/mL compared to Gifitinib (IC50 = 0.05 µg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.

Molecular hybrids: A five-year survey on structures of multiple targeted hybrids of protein kinase inhibitors for cancer therapy.

Protein kinases have grown over the past few years as a crucial target for different cancer types. With the multifactorial nature of cancer, and the fast development of drug resistance for conventional chemotherapeutics, a strategy for designing multi-target agents was suggested to potentially increase drug efficacy, minimize side effects and retain the proper pharmacokinetic properties. Kinase inhibitors were used extensively in such strategy. Different kinase inhibitor agents which target EGFR, VEGFR, c-Met, CDK, PDK and other targets were merged into hybrids with conventional chemotherapeutics such as tubulin polymerization and topoisomerase inhibitors. Other hybrids were designed gathering kinase inhibitors with targeted cancer therapy such as HDAC, PARP, HSP 90 inhibitors. Nitric oxide donor molecules were also merged with kinase inhibitors for cancer therapy. The current review presents the hybrids designed in the past five years discussing their design principles, results and highlights their future perspectives.

New nicotinic acid-based 3,5-diphenylpyrazoles: design, synthesis and antihyperlipidemic activity with potential NPC1L1 inhibitory activity.

Nicotinic acid hydrazide was incorporated into new 4,5-dihydro-5-hydroxy-3,5-diphenylpyrazol-1-yl derivatives. Compounds 6a-h were synthesized, and their antihyperlipidemic activity was evaluated in high cholesterol diet-fed rat model. Compounds 6e, 6f were found to decrease the levels of serum total cholesterol by 14-19% compared to control group. Total triglycerides were also reduced by 24-28% and LDL cholesterol by 16%. As expected from parent niacin, compounds 6e and 6f caused an elevation of HDL cholesterol by 33-41%. Docking study supported the ability of designed compounds to block NPC1L1 active site in a manner similar to that observed with ezetimibe.

Densely functionalized cinnolines: Controlled microwave-assisted facile one-pot multi-component synthesis and in vitro anticancer activity via apoptosis induction.

There is an urging continuous need for novel anti-cancer agents due to persistent chemoresistance. Herein, newly synthesized cinnolines are evaluated for their possible anticancer activities and suggested mechanisms. In the current study, a simple and efficient synthesis of densely functionalized cinnolines has been developed that relied on multi-component reaction of ethyl 5-cyano-4-methyl-1-aryl-6-oxo-1,6-dihydropyridazine-3-carboxylates with aromatic aldehydes and nitromethane in dioxane/pipridine under controlled microwave heating. Selected cinnolines (4a-c, e, h, j-n, q-v) were tested for possible anticancer activity using in vitro one dose assay at National Cancer institute, USA. Only cinnoline 4b stood out as the most potent cinnoline derivative (mean GI%=26.33) with broad-spectrum antitumor activity against the most tested cancer cell lines from all subpanels. The target cinnoline 4b emerged as the most active derivative against both leukemia RPMI-8226 and melanoma LOX IMVI cell lines (GI% = 106.06 and 82.1) respectively, with IC50 values equal to 17.12 ± 1.31 and 12.32 ± 0.75 µg/mL, which are comparable to those of staurosporin; 24.97 ± 1.47 and 8.45 ± 0.42 µg/mL, respectively. Cinnoline 4b influenced cell cycle distribution causing pre-G1 apoptosis and cell growth arrest at G2/M phase. It also induced apoptosis in both cell lines as manifested by significant increase in the percent of annexin V-FITC positive apoptotic cells in leukemia RPMI-8226 cells (from 1.09% to 12.47%) and melanoma LOX IMVI (from 1.32% to 19.05%). In addition, it showed lower expression levels of anti-apoptotic Bcl-2 protein, and higher expression levels of pro-apoptotic proteins; Bax, p53, cytochrome c, caspases 3 and 9. CONCLUSION: Induction of mitochondrial intrinsic pathway of apoptosis is a possible mechanism by which cinnoline 4b may confer its anticancer activity.

Potential repurposed SARS-CoV-2 (COVID-19) infection drugs.

The global outbreak of COVID-19 viral infection is associated with the absence of specific drug(s) for fighting this viral infection. About 10 million people are already infected, about 500 000 deaths all over the world to date. Great efforts have been made to find solutions for this viral infection, either vaccines, monoclonal antibodies, or small molecule drugs; this can stop the spread of infection to avoid the expected human, economic and social catastrophe associated with this infection. In the literature and during clinical trials in hospitals, several FDA approved drugs for different diseases have the potential to treat or reduce the severity of COVID-19. Repurposing of these drugs as potential agents to treat COVID-19 reduces the time and cost to find effective COVID-19 agents. This review article summarizes the present situation of transmission, pathogenesis and statistics of COVID-19 in the world. Moreover, it includes chemistry, mechanism of action at the molecular level of the possible drug molecules which are liable for redirection as potential COVID-19 therapeutic agents. This includes polymerase inhibitors, protease inhibitors, malaria drugs, lipid lowering statins, rheumatoid arthritis drugs and some miscellaneous agents. We offer research data and knowledge about the chemistry and biology of potential COVID-19 drugs for the research community in this field.

New quinoline/chalcone hybrids as anti-cancer agents: Design, synthesis, and evaluations of cytotoxicity and PI3K inhibitory activity.

A series of quinoline-chalcone hybrids was designed as potential anti-cancer agents, synthesized and evaluated. Different cytotoxic assays revealed that compounds experienced promising activity. Compounds 9i and 9j were the most potent against all the cell lines tested with IC50 = 1.91-5.29 µM against A549 and K-562 cells. Mechanistically, 9i and 9j induced G2/M cell cycle arrest and apoptosis in both A549 and K562 cells. Moreover, all PI3K isoforms were inhibited non selectively with IC50s of 52-473 nM when tested against the two mentioned compounds with 9i being most potent against PI3K-γ (IC50 = 52 nM). Docking of 9i and 9j showed a possible formation of H-bonding with essential valine residues in the active site of PI3K-γ isoform. Meanwhile, Western blotting analysis revealed that 9i and 9j inhibited the phosphorylation of PI3K, Akt, mTOR, as well as GSK-3ß in both A549 and K562 cells, suggesting the correlation of blocking PI3K/Akt/mTOR pathway with the above antitumor activities. Together, our findings support the antitumor potential of quinoline-chalcone derivatives for NSCLC and CML by inhibiting the PI3K/Akt/mTOR pathway.

Spirohydantoins and 1,2,4-triazole-3-carboxamide derivatives as inhibitors of histone deacetylase: Design, synthesis, and biological evaluation.

Two structurally novel series of histone deacetylase inhibitors (HDACIs) involving two potential surface recognition moieties; 3',4'-dihydro-2'H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione (in series I) and 1-(3-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide (in series II) were designed, synthesized, and evaluated for their anti-proliferative activities, HDAC inhibitory activities, and their binding modes to HDAC protein. Compounds 5f and 10e showed comparable HDAC inhibitory activity to SAHA. Series II have been also demonstrated as potential HDAC-tubulin dual inhibitors, promoted with structural similarities between (1-(3-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide) nucleus, of series II, and Combretastatin A4. The tubulin inhibitory activities of series II members, together with their docking into colchicine binding site of ß-tubulin were performed. Compound 9a showed remarkable cytotoxicity. Hybrid 10e behaved as potent HDAC-tubulin dual inhibitor. It showed better tubulin inhibition than CA4 as well as its effectiveness against HDAC.

New 1,3,4-oxadiazole/oxime hybrids: Design, synthesis, anti-inflammatory, COX inhibitory activities and ulcerogenic liability.

A series of new 1,3,4-oxadiazole/oxime hybrids were synthesized and designed as potent COX inhibitors. The prepared compounds were evaluated for their anti-inflammatory, antioxidant and ulcerogenic activities. The results indicated that the prepared compounds exhibited remarkable anti-inflammatory activity with (69.60-109.60% of indomethacin activity) after 4h. In vitro COX inhibitory assay showed that compounds 6d and 7h are potent COX inhibitors with IC50 of (1.10-0.94) and (2.30-5.00) µM on both COX-1 and COX-2 respectively. Compound 7h was found to inhibit both COXs non-competitively with Ki values of 73µM and 89µM. Most of the tested compounds showed ulcer-free stomachs compared to indomethacin.

Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis, docking studies and investigation of anti-inflammatory, ulcerogenic liability and analgesic activities.

A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC50s of 0.75-70.50µM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.

Nitroxyl (HNO): A Possible Strategy for Fighting Cancer.

Nitroxyl (HNO), the one electron reduced form of nitric oxide (NO), shows a very distinct chemistry and biology from that of NO. Chemical profile is characterized by reactions with thiols and thiol proteins such as aldehyde dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, caspases among others. Biological profile of HNO includes cardioprotective actions especially in cases of heart failure. This short review focuses on the cytotoxic properties for HNO. Nitroxyl was found to be toxic to several cancer cell lines including lung and breast cancers. Critical thiols that control cancer cellular functions might be the target for HNO activity. The anti-tumor actions of HNO donating aspirin is also summarized.

Nitroxyl (HNO): A Reduced Form of Nitric Oxide with Distinct Chemical, Pharmacological, and Therapeutic Properties.

Nitroxyl (HNO), the one-electron reduced form of nitric oxide (NO), shows a distinct chemical and biological profile from that of NO. HNO is currently being viewed as a vasodilator and positive inotropic agent that can be used as a potential treatment for heart failure. The ability of HNO to react with thiols and thiol containing proteins is largely used to explain the possible biological actions of HNO. Herein, we summarize different aspects related to HNO including HNO donors, chemistry, biology, and methods used for its detection.