Discovery of novel pyrazole and pyrazolo[1,5-a]pyrimidine derivatives as cyclooxygenase inhibitors (COX-1 and COX-2) using molecular modeling simulation.

Searching for effective and selective anti-inflammatory agents, our study involved designing and synthesizing new pyrazole and pyrazolo[1,5-a]pyrimidine derivatives 4-11. The structures of the synthesized derivatives were confirmed using different spectroscopic techniques. Virtual screening was achieved for the newly designed derivatives using in silico docking simulation inside the active sites of four proteins classified as two cyclooxygenases (COX)-1 (PDB: 3KK6 and 4OIZ) and two COX-2 (PBD: 1CX2 and 3LN1). Among them, six derivatives 4c, 5b, 6a, 7a, 7b, and 10b displayed the highest binding energy. These derivatives were evaluated for their in vitro COX-1 and COX-2 inhibitory activities and their selectivity indexes were calculated. Additionally, these derivatives displayed IC50 values ranging between 4.909 ± 0.25 and 57.53 ± 2.91 µM, and 3.289 ± 0.14 and 124 ± 5.32 µM, against COX-1 and COX-2, respectively. Furthermore, the tested derivatives were found to have selective inhibitory activity on the COX-2 enzyme. Surprisingly, the two pyrazole derivatives 4c and 5b were found to be the most active, with IC50 values of 9.835 ± 0.50 and 4.909 ± 0.25 µM and 4.597 ± 0.20 and 3.289 ± 0.14 µM compared with meloxicam (1.879 ± 0.1 and 5.409 ± 0.23 µM) and celecoxib (5.439 ± 0.28 and 2.164 ± 0.09 µM) against COX-1/-2, respectively. Besides, two pyrazole derivatives, 4c and 5b, displayed a COX-1/COX-2 SI of 2.14 and 1.49. Computational techniques such as molecular docking, density function theory (DFT) calculation, and chemical absorption, distribution, metabolism, excretion, and toxicity evaluation were applied to explain the molecules' binding mode, chemical nature, drug likeness, and toxicity prediction.

Development of novel pyrazole, imidazo[1,2-b]pyrazole, and pyrazolo[1,5-a]pyrimidine derivatives as a new class of COX-2 inhibitors with immunomodulatory potential.

Searching for new compounds with anti-inflammatory properties is a significant target since inflammation is a major cause of pain. A series of pyrazole, imidazopyrazolone, and pyrazolopyrimidine derivatives were designed and synthesized by reaction of 3,5-diamino-1H-pyrazole derivative with cyclic and acyclic carbonyl reagents. The structure of the newly synthesized derivatives were fully characterized using different spectroscopic data and elemental analysis, and therefore, evaluated as COX-2 inhibitors. The in vitro COX-2 activity of the tested derivatives 2-13 displayed moderate to good potency with two derivatives 8 and 13 that exhibiting high potency to COX-2 with IC50 values of 5.68 ± 0.08 and 3.37 ± 0.07 µM compared with celecoxib (IC50 = 3.60 ± 0.07 µM) and meloxicam (IC50 = 7.58 ± 0.13 µM). Furthermore, the most active pyrazolo[1,5-a]pyrimidine derivatives 8 and 13 were evaluated to measure the levels of pro-inflammatory proteins such as TNF-α and IL-6 using qRT-PCR in RAW264.7 cells, and the results showed down-regulation of two immunomodulatory proteins. Surprisingly, these derivatives 8 and 13 revealed a decrease in IL-6 level with inhibition percentages of 65.8 and 70.3%, respectively, compared with celecoxib (% = 76.8). Further, compounds 8 and 13 can regulate and suppress the TNF-α with percentage inhibition of 63.1 and 59.2% to controls, while celecoxib displayed an inhibition percentage of 72.7. The Quantum chemical calculation was conducted, and data explained the structural features crucial to the activity. The molecular docking simulation and ADMET predictions revealed that the most active derivatives have good binding affinity, possess appropriate drug-likeness properties and low toxicity profiles. Finally, compounds 8 and 13 demonstrated COX-2 inhibitors with α-TNF and IL-6 suppression capabilities as a dual-action strategy to get more effective treatment.

Application of acid modified polyurethane foam surface for detection and removing of organochlorine pesticides from wastewater.

The commercial polyurethane foam was acid modified to get an inexpensive adsorbent (AM-PUF) has highly surface polarity and sorption capacity. The elemental analysis, scanning electron microscopy, thermal analysis, ultraviolet/visible/infrared spectroscopies and X-ray diffraction were used for characterization of AM-PUF. The surface of AM-PUF has amorphous character (broadband at 2θ, 21.75°) and contains several active sites e.g. NH, OH, CO, CC and COC groups. The electrical conductivity (σ), iodine value and methylene blue index of AM-PUF are 1.7×10-5Ω-1m-1, 208mg/g and 107mg/g. The AM-PUF has a high efficiency for completely removing (99-100%) of Aldrin, DDT, Endrin, Heptachlor, Heptachlor epoxide and Lindane pesticides in both acidic and alkaline solutions. The removing rates of the organochlorine pesticides from wastewater are very rapid (t1/2=22s). The negative value of ΔG (-10.9kJ/mol) for removing of OCPs using AM-PUF showed that the feasibility of the removing process and its spontaneous nature.

Prevalence and pathogenesis of some filarial nematodes infecting donkeys in Egypt.

AIM: The primary objective of the present study is to determine the commonness of filarial parasites in donkeys in Egypt, identification of the filarial species tainting them and the delivered pathogenic impact connected with the infestation. MATERIALS AND METHODS: A total of 188 donkeys were examined for filarial infection. The blood samples and scraping of the cutaneous bleeding lesions were collected, stained, and inspected for microfilariae all through the period from March 2011 to October 2013. The adult worms were perceived in tissue samples acquired from skin scraping, testes, eyes, tendons, peritoneal and pleural cavities, and the ligamentum nuchae. RESULTS: On the basis of morphological identification, 163 of 188 donkeys (86.70%) were infected with Onchocerca cervicalis (82.98%), Setaria equina (31.11%), Parafilaria multipapillosa (5.32%), and Onchocerca reticulata (4.26%). There was no significant effect of the sex on the incidence of all the encounteredfilarial worms except for S. equina, where the infection rate prevailed in males versus females (40.82% vs. 35.90%). In addition, age group of 5-15 years old exhibited a fundamentally higher predominance (p< 0.05) of the recognized filarial worms versus those of < 5 years old and >15 years old. CONCLUSION: The preliminary results add to our comprehension of filarial species infecting donkeys in Egypt, their impact on animal execution and production. Accentuation must be taken for avoidance, control of filarial disease, and improvement of the management system of donkeys.

Pharmacological effects of althesin and its steroidal components on the cardiovascular system.

Althesin and its two steroidal components elicited, despite a deficit vasopressor effect by their solvent vehicle Cremophor El, a well-marked hypotensive activity appearing abruptly after i.v. injection in chloralosed cats. This vasodepressor effect which was weaker and shorter lasting with alphadolone acetate than alphaxalone proved to be one-cholinergic, nonhistaminergic, not mediated via any ganglionic blocking activity and ;mostly attributable to central depressant action on vasomotor tone. An appreciable direct myocardial inhibition and a much weaker direct peripheral vasodilatation were shown to be contributory factors to the hypotension. ECG studies in chloralosed cats indicated the occurrence of mild grade bradycardia or else no evident change in the heart rate under the influence of althesin and its steroidal components. A definite protective influence for althesin mainly due to alphaxalone against adrenaline induced arrhythmia in chloralosed cats was also demonstrated.