Investigation of the anti-inflammatory and analgesic activities of promising pyrazole derivative.

The development of new COX-2 inhibitors with analgesic and anti-inflammatory efficacy as well as minimal gastrointestinal, renal and cardiovascular toxicity, is of vital importance to patients suffering from chronic course pain and inflammatory conditions. This study aims at evaluating the therapeutic activity and adverse drug reactions associated with the use of the newly synthesized pyrazole derivative, compound AD732, E-4-[3-(4-methylphenyl)-5-hydroxyliminomethyl-1H-pyrazol-1-yl]benzenesulfonamide, as compared to indomethacin and celecoxib as standard agents. Anti-inflammatory activity was assessed using carrageenan-induced rat paw edema and cotton pellet granuloma tests; formalin-induced hyperalgesia and hot plate tests were done to study analgesic activity. In vitro tests to determine COX-1/COX-2 selectivity and assessment of renal and gastric toxicity upon acute exposure to AD732 were also conducted. Compound AD732 exhibited promising results; higher anti-inflammatory and analgesic effects compared to standard agents, coupled with the absence of ulcerogenic effects and minimal detrimental effects on renal function. Additionally, compound AD732 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It may be concluded that compound AD732 appears to be a safer and more effective molecule with promising potential for the management of pain and inflammation.

Synthesis, in silico experiments and biological evaluation of 1,3,4-trisubstituted pyrazole derivatives as antimalarial agents.

New 1,3,4-trisubstituted pyrazole derivatives were synthesized and evaluated for their antiplasmodial activity. Compounds 4b, 4c, 7a and 7d were the most potent antiplasmodial agents against P. berghei with percent of suppression ranging from 90 to 100%. They were also screened for their in vitro antimalarial activity against the chloroquine resistant strain P. falciparum, (RKL9). Compound 4c displayed the highest in vitro antimalarial activity; 13-fold higher than standard chloroquine phosphate. Molecular docking of the most active compounds against the wildtype and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Furthermore, these compounds exhibited reasonable in silico drug-likeness and pharmacokinetic properties. Toxicity studies of the most active compounds revealed that all tested compounds were non-toxic and well-tolerated up to 150 mg/kg via oral route and 75 mg/kg via parentral route. According to RBC hemolysis assay, it was found that compound 7a was the most potent anti-inflammatory and least toxic derivative with IC50 value 71-fold higher than IC50 value related to the antimalarial activity. Moreover, cytotoxicity assessment revealed that compound 4c was the least toxic derivative with IC50 value 70000-fold higher than IC50 value related to the antimalarial activity.

Lactoperoxidase catalyzes in vitro activation of acrylonitrile to cyanide.

Acrylonitrile (ACN) is a widely used industrial chemical. Although it is a well reported animal carcinogen, its current designation to humans is "possibly carcinogenic". The present study aimed at investigating the ability of LPO enzyme system to oxidize ACN to cyanide (CN(-)) in vitro. Detection of CN(-) served as a marker for the possible generation of free radical intermediates implicated in ACN induced toxicity in the activation process. Optimum conditions for the oxidation of ACN to CN(-) were characterized with respect to pH, temperature and time of incubation as well as ACN, LPO and H(2)O(2) concentrations in incubation mixtures. Maximum reaction velocity (V(max)) and Michaelis-Menten constant (K(m)) were assessed. Addition of nitrite (NO(2)(-)) salts to the reaction mixtures significantly enhanced the rate of the reaction. Free radical scavengers (quercetin and trolox C), LPO enzyme inhibitor (resorcinol) and competitors for LPO binding (sodium azide and indomethacin) were found to reduce the rate of CN(-) production. Inclusion of the sulfhydryl compounds glutathione (GSH), NAC (N-acetylcysteine), D-penicillamine or L-cysteine enhanced the rate of ACN oxidation. The present results demonstrate the ability of LPO enzyme system to oxidize ACN to CN(-) and provide insight for the elucidation of ACN chronic toxicity.