Regioselective synthesis, biological evaluation, and molecular docking of dihydropyrimidin-4-ols as acetylcholinesterase inhibitors.

A new series of 3,6-disubstituted 2-(methylthio)-4-(trifluoromethyl)-3,4-dihydropyrimidin-4-ols displaying methyl, phenyl, aryl, and heteroaryl groups at the 6-position; and methyl, ethyl, allyl, and phenyl groups at the 3-position of the dihydropyrimidine ring, were synthesized and evaluated in vitro for acetylcholinesterase inhibitory activity. Seven compounds showed activity with IC50 values in the lower micromolar range. The compound 4-trifluoromethyl-6-(4-fluorophenyl)-3-methyl-2-methylthio-3,4-dihydropyrimidin-4-ol (6e) had the best inhibitory activity (IC50 2.2 ± 0.9 µm) and this inhibition was characterized as competitive. The molecular docking study showed that the acetylcholinesterase enzyme accommodates compound 6e in its catalytic site. The enantiomers of compound 6e, present similar interactions: π-π stacking interactions between the aromatic ring of the ligand's 4-fluorophenyl moiety and the aromatic rings of the electron-rich Trp84; and H-bonds between the hydroxyl group of Tyr121 and the hydroxyl moiety from 6e. The antioxidant effect of the dihydropyrimidin-4-ols was also investigated.

Chemical composition and evaluation of acute toxicological, antimicrobial and modulatory resistance of the extract of Murraya paniculata.

CONTEXT: Murraya paniculata (Linn) JACK (Rutaceae) is used in traditional medicine in the treatment of diabetes, inflammation, and microbial disorders. OBJECTIVE: This study determined the polyphenol composition and antimicrobial and acute toxicological activity of the hydroethanolic extract of M. paniculata leaves (EEMp). MATERIALS AND METHODS: Chemical composition was evaluated by the Folin-Ciocalteu and AlCl3 assays and by HPLC-DAD. Antibacterial and modulatory activity was determined by the microdilution method. Toxicity was assessed with a single dose of EEMp administered orally at doses of 2000 and 5000 mg/kg body weight/day in male and female Swiss mice. RESULTS: Total phenolic content of the EEMp samples varied from 66.5 to 396.8 mg gallic acid equivalent/g of extract and flavonoid content varied from 0.3 to 31.1 mg quercetin equivalent/g of extract. The principal component identified by HPLC-DAD assay was ellagic acid. The results of oral acute toxicity showed no mortality, changes in hematological parameters, or CNS and ANS toxicities in rats. Biochemical analysis showed a significant increase in glucose and glutamic oxaloacetic transaminase activity and reduction in triglycerides and cholesterol for 5000 and 2000 mg/kg doses, respectively, when compared with the control group. Histopathological evaluation showed no significant microscopic changes. EEMp showed essentially no antimicrobial activity, but when aminoglycosides were combined with EEMp their MIC was reduced. CONCLUSIONS: Significant effects were observed in the acute toxicity assay, but they had no clinical relevance. The results suggest that M. paniculata could be used as a source of natural products with antibacterial resistance-modifying activity, with lower toxicity.

Topical anti-inflammatory effect of Caryocar coriaceum Wittm. (Caryocaraceae) fruit pulp fixed oil on mice ear edema induced by different irritant agents.

AIM OF THE STUDY: Caryocar coriaceum Wittm. fruit pulp fixed oil (CCFO) has been widely employed by communities from Brazil Northeastern in the treatment of skin inflammation, respiratory affections, wound healing and muscle pain. In this study, we evaluated the topical effect of CCFO against different irritant agents in vivo, in order to verify its antiedematous effect as well to unravel its tentative mechanisms of action. MATERIALS AND METHODS: CCFO was obtained from Caryocar coriaceum fruits using ethyl acetate as solvent. Ear edema provoked by the application of Croton oil (single and multiple applications), arachidonic acid (AA), capsaicin, phenol and histamine to Swiss mice was used to evaluate the topical anti-inflammatory effect of CCFO. Histological analysis from mice ears sensitized with Croton oil and AA single application was also performed. RESULTS: Crude CCFO (20µL/ear) demonstrated significant topical antiedematous effect against Croton oil single (inhibition of 32.0%; P<0.05) and multiple (41.4% after 9 days, P<0.001) applications, AA (inhibition of 49.7%; P<0.01) and phenol (inhibition of 38.8%; P<0.001). In contrast, CCFO did not antagonize the edema caused by topical treatment with capsaicin and histamine when compared to control group (P>0.05). Histological analysis also revealed that CCFO was able to reduce the edema and the influx of inflammatory cells in mice ears sensitized with Croton oil and AA. CONCLUSIONS: CCFO exhibited a similar profile of topical anti-inflammatory activity to that of drugs that classically modulate the production of arachidonic acid metabolites. The study also indicates the potential application of CCFO as an important herbal medicine to be used against skin inflammatory diseases.

Topical anti-inflammatory activity of body fat from the lizard Tupinambis merianae.

AIM OF THE STUDY: Tupinambis merianae is one of the most frequently used animals in traditional medicine in Brazil as its body fat has many different therapeutic indications as a folk remedy. The present study evaluated the topical anti-inflammatory activity of Tupinambis merianae fat in treating ear edema in an animal model. MATERIALS AND METHODS: Oil (OTM) was extracted from body fat located in the ventral region of Tupinambis merianae using hexane as a solvent. Ear edema provoked by the application of croton oil (single and multiple application), arachidonic acid, phenol and capsaicin to Swiss mice was used to evaluate the potential anti-inflammatory value of the topical use of OTM. Topical applications of these irritants were made to the right ears of animals that were pre-treated with a acetone (control), dexamethasone, or OTM. RESULTS: Our results indicate that Tupinambis merianae fat demonstrates significant topical antiinflammatory activity that reduces inflammation related to ear edema caused by croton oil (single and multiple application), arachidonic acid, phenol. While the inflammation caused by capsaicin, OTM did not significantly reduce the edema. CONCLUSION: This represents the first evidence of anti-inflammatory activity of Tupinambis merianae fat in in vivo models, confirming its usefulness in traditional medicine as a remedy for skin diseases (dermatitis). The fatty acids present in OTM most likely inhibit the response pathway of arachidonic acid and its metabolites, thus reducing the production of pro-inflammatory mediators.