New pyranocoumarin and coumarin-sulfonamide derivatives were prepared and evaluated for their antioxidant, antimicrobial, and/or anti-inflammatory activities. Coumarin-sulfonamide compounds 8a–d demonstrated significant antioxidant activity, while 7c,d, 8c,d, and 9c,d exhibited antimicrobial activity equal to or higher than the standard antimicrobials against at least one tested microorganism. Regarding the anti-inflammatory testing, pyranocoumarins 2b, 3a,b and 5c and coumarin-sulfonamide compound 9a showed more potent antiproteinase activity than aspirin in vitro; however, five compounds were as potent as aspirin. The anti-inflammatory activity of the promising compounds was further assessed pharmacologically on formaldehyde-induced rat paw oedema and showed significant inhibition of oedema. For in vitro COX-inhibitory activity of coumarin derivatives, pyranocoumarin derivative 5a was the most selective (SI = 152) and coumarin-sulfonamide derivative 8d was most active toward COX-2 isozyme. The most active derivatives met the in silico criteria for orally active drugs; thus, they may serve as promising candidates to develop more potent and highly efficient antioxidant, antimicrobial, and/or anti-inflammatory agents.

Background: Diethylnitrosamine (DENA), a well-known dietary carcinogen, related to cancer initiation of variousorgans. The present study investigated the deleterious mechanisms involved in the early destructive changes of DENAin different organs namely, liver, stomach and colon and the potential protective effect of GE against these mechanisms.Methods: Adult male albino rats were assigned into four groups. A normal control group received the vehicle, anothergroup was injected with a single necrogenic dose of DENA (200 mg/kg, i.p) on day 21. Two groups received oral GE(108 or 216 mg/kg) daily for 28 days. Sera, liver, stomach and colon were obtained 7 days after DENA injection. Serumaspartate transaminase and alanine transaminase were detected as well as reduced glutathione (GSH), malondialdehyde,nitric oxide metabolites, interleukin 1β, tumor necrosis factor (TNF-α), alpha-fetoprotein (AFP) and nuclear factorerythroid2-related factor2 (Nrf2) in liver, stomach and colon. Histopathological studies and immunohistochemicalexamination of cyclooxygenase-2 (COX2) were conducted. Results: DENA induced elevation in liver function enzymeswith significant increase in oxidation and inflammation biomarkers and AFP while decreased levels of Nrf2 in liver,stomach and colon were detected. Histologically, DENA showed degenerative changes in hepatocytes and inflammatoryfoci. Inflammatory foci displayed increased expression of COX2 in immunohistochemical staining. GE-pretreatmentimproved liver function and restored normal GSH with significant mitigation of oxidative stress and inflammatorybiomarkers compared to DENA-treated group. AFP was reduced by GE in both doses, while Nrf2 increased significantly.Histology and immunostaining of hepatic COX-2 were remarkably improved in GE-treated groups in a dose dependentmanner. Conclusion: GE exerted a potential anti-proliferative activity against DENA in liver, stomach and colon viaNrf2 activation, whilst suppression of oxidation and inflammation.

Diabetes is the most common metabolic disorder in both developing and non-developing countries, and a well-recognized global health problem. The WHO anticipates an increase in cases from 171 million in 2000 to 366 million by 2030. In the present study, we focus on the preparation of pyrimidine derivatives as potential antidiabetic and antimicrobial agents. Thein vivoeffect on total serum glucose concentration, cholesterol and antioxidant activity was assessed in adult male albino Wister rats and compared to the reference drug glimperide. Promising results were observed for compound 5. The histopathological study confirms that compound 5 results in significant activity with liver maintenance. The antimicrobial activities were evaluated against several bacterial strains such as Salmonella typhimurium ATCC 25566, Bacillus cereus, Escherichia coli NRRN 3008, Pseudomonas aeruginosa ATCC 10145, Staphylococcus aureus ATCC 6538and fungi such as Rhizopus oligosporus, Mucor miehei and Asperillus niger. Compounds 4 and 5 showed a good inhibition of the bacterial zone compared to the reference drug cephradine. Finally, we suggest protein targets for these drugs based on computational analysis, and infer their activities from their predicted modes of binding using molecular modeling. The molecular modeling for compounds 4 and 5 resulted in improved docking scores and hydrogen bonding. The docking studies are in good agreement with the in vitro and in vivo studies.

Fruit by-products are considered nature's golden gift for human health and a good starting point to discover new drugs depending on the fact that they contain millions of bio-active compounds that are responsible for therapeutic activities. In this context, the main goal of this study is to recycle Citrus aurantium (C. aurantium) seeds to produce pharmaceutical molecules to be used in the prevention of the progressive neurological damage associated with Alzheimer disease (AD). Donepezil (0.75 mg/kg), hesperidin (125 and 250 mg/kg) and limonoids (50 and 100 mg/kg) were used for treatment of rats for 2 weeks prior to concomitant administration of AlCl₃ for three successive weeks. Protection against cognitive deterioration was observed among study group with insignificant difference from normal control group and significant difference from positive control group in the Y-Maze test. On the other hand, treatment with both doses of hesperidin (125 and 250 mg/kg) and high dose of limonoids only (100 mg/kg) produced improvement in psychological state, observed by significant increase in ambulation frequency in comparison to positive control group, however it was not as frequent as normal group, as it was significantly less than normal group in the open field test. Regarding acetylcholine esterase (AChE) and beta-amyloid (β amyloid) levels, the effect of limonoids low dose was the best as it didn't have a significant effect when compared to normal control, also hesperidin in both doses showed insignificant effects on β amyloid levels when compared to normal control group. Our results encourage the use of C. aurantium seeds which are wasted in huge amounts, as Alzheimer prophylactic food additives.

Brain damage caused by cerebral ischaemia/reperfusion (I/R) can lead to handicapping. So, the present study aims to evaluate the prophylactic and therapeutic effects of geraniol in the form of intranasal polymeric mixed micelle (PMM) on the central nervous system in cerebral ischaemia/reperfusion (I/R) injury. A 3² factorial design was used to prepare and optimize geraniol PMM to investigate polymer and stabilizer different concentrations on particle size (PS) and percent entrapment efficiency (%EE). F3 possessing the highest desirability value (0.96), with a PS value of 32.46 ± 0.64 nm, EE of 97.85 ± 1.90%, and release efficiency of 59.66 ± 0.64%, was selected for further pharmacological and histopathological studies. In the prophylactic study, animals were classified into a sham-operated group, a positive control group for which I/R was done without treatment, and treated groups that received vehicle (plain micelles), geraniol oil, and geraniol micelles intranasally before and after I/R. In the therapeutic study, treated rats received geraniol oil and micelles after I/R. Evaluation of the effect of geraniol on behavior was done by activity cage and rotarod and the analgesic effect tested by hot plate. Anti-inflammatory activity was assessed by measuring interleukin β6, cyclooxygenase-2, hydrogen peroxide, and inducible nitric oxide synthase. Histopathogical examination of cerebral cortices was also done to confirm the results of a biochemical assay. Geraniol nanostructured polymeric mixed micelles showed an enhanced neuro-protective effect compared to geraniol oil, confirming that PMM via intranasal route could be an efficient approach for delivering geraniol directly to the brain through crossing the blood–brain barrier.