Wafaa I. El-Eraky

Synthesis, vasorelaxant activity, and molecular modeling study of some new phthalazine derivatives.

New phthalazine-based vasodilators were synthesized through the chloroacylation of the starting compound 1-hydrazinophthalazine 4 to give the two key intermediates 5 and 7. These intermediates were used to alkylate various cyclic amines to furnish the final compounds 6a-h and 8a-h. Compounds were tested for their vasorelaxant activities against nor-adrenaline-induced spasm on thoracic rat aorta rings and compared to the reference drug, prazosin. Seven compounds showed higher activity than prazosin, especially compound 8d having an IC(50)=0.10 mM. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as α(1)-AR antagonists showed high docking score and fit values. Most vasodilation activities of tested compounds are consistent with their molecular modeling results.

Molecular structure studies of novel bronchodilatory-active 4-azafluorenes

Abstract Two 5H-indeno[1,2-b]pyridines, 7a and 7b, were synthesized and characterized by X-ray crystallography. In the molecular packing, molecules of 7a are linked into chains by C–H···N hydrogen bond which, in turn, are connected by H···π, N···π, Cl···π and π···π interactions. In the crystal structure of 7b, molecules are connected by C–H···N and C–H···Cl interactions as well as a set of N···π and Cl···π interactions. The molecular structures were studied by theory using AM1, PM3 and DFT. The basic difference between the theoretical and experimental structures was found in the relative orientation of dichlorophenyl ring attached to the indenopyridine residue, which was revealed to be aligned in nearly opposite orientations. This observation is attributed to the bulky chlorine atom(s) of the phenyl ring that prevent free rotation around the sigma bond attaching this ring with the heterocyclic system. DFT was used to determine the molecular electrostatic potential revealing the nitrile nitrogen to be the most nucleophilic site. A low HOMO-LUMO energy gap indicates high reactivity of 7a and 7b. The synthesized azafluorenes show more potent bronchodilation properties than the standard reference compound (theophylline).

Crystal Structure Studies and Bronchodilation Properties of Novel Benzocycloheptapyridines

Benzocycloheptapyridines 6a and 6b were characterized by single crystal X-ray diffraction. Molecular packing exhibits that, molecules of compound 6a are linked in chains by one hydrogen bond of C–H···N type and set of H–π, and Cl–π interactions. However, compound 6b is stabilized by only Cl–π interactions. The main conformational difference between the experimental and theoretical optimized structures (using AM1, PM3 and DFT) was found in the relative orientation of the dichlorophenyl ring attached to the benzocycloheptapyridine system, which is attributed to the effect of the bulky chloride atom that prevents free rotation around the sigma bond attaching this ring with the heterocyclic system. Also, the lattice form plays an important role affecting the observed conformation. A similar behavior is also exhibited for the methyl group of the ethoxy function of 6b. The synthesized 6a reveals bronchodilation potency greater than that of the standard reference used, theophylline.Graphical AbstractBenzocycloheptapyridines were characterized by single crystal X-ray diffraction. Computational chemistry studies (AM1, PM3 and DFT) support the molecular structures. The synthesized analogues reveal promising bronchodilation properties.

Cardiorenal protective effect of taurine against cyclophosphamide-induced toxicity in albino rats.

Cyclophosphamide (CP) is a cytotoxic alkylating agent used in the treatment of malignant diseases and autoimmune disorders. Its clinical use is limited to its marked cardiorenal toxicity. The present study aimed to investigate the possible protective role of taurine (Tau; 200 mg·kg-1 per day, i.p.) on CP-induced cardiorenal toxicity. CP (200 mg·kg-1) was administered as a single intraperitoneal injection whereas; Tau was administered for 3 weeks on a daily basis. The results showed that CP produced an elevation in serum activities of creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase, creatinine as well as blood urea nitrogen. CP also induced an elevation in the oxidative stress markers viz. elevation in the serum lipid peroxides level (measured as malondialdehyde; MDA) and reduction in reduced glutathione level and superoxide dismutase activity in both heart and renal tissue. On the other hand, administration of Tau attenuated the CP-evoked disturbances in the above mentioned parameters. In addition, CP exhibited electrocardiographic (ECG) changes, which were significantly reversed by Tau treatment. Finally, the histopathological examination emphasized the obtained results. In conclusion, Tau is suggested to be a potential candidate to ameliorate CP-induced cardiorenal toxicity that may be related to its antioxidant activity.

Evaluation of the effects of Eserine and JWH-133 on brain dysfunction associated with experimental endotoxemia

UNLABELLED Sepsis is associated with neuronal damage and cognitive impairment, with the participation of pro-inflammatory cytokines and oxidative-nitrous stress. It is known that activated microglia plays a vital role in neuro-inflammation and neuro-degeneration. Thus, the objective of this study was to evaluate therapeutic roles of two microglia regulating agents, JWH-133 and Eserine, on the neuroinflammatory associated brain dysfunctions. To achieve our aim, we used control rats or submitted rats to lipopolysaccharide (LPS) challenge. 30 min after LPS challenge, the animals received either saline, Eserine, JWH-133 or Eserine+JWH-133. After 24h, animals were submitted to the habituation to T maze, Rotarod and activity cage tests. The rats were killed after and were evaluated for central and peripheral inflammatory and oxidative parameters. We observed that the use of Eserine, JWH-133 or Eserine + JWH-133 reverted the increases in the inflammatory markers [interleukin 6 (IL6), vascular cell adhesion molecule 1(VCAM-1) and Eselectin] and oxidative-nitrous stress MDM, and that the anti-inflammatory, antioxidant properties of both JWH-133 and Eserine successfully improve the LPS induced brain dysfunction. CONCLUSIONS The results observed in this study reinforce the role of microglia activation regulating agents, in particular, JWH-133 and Eserine, in the brain dysfunction associated with endotoxemia.

Pyridazine and its related compounds. Part 34. Hypoglycemic and hypolipidemic activity of some novel condensed pyridazine sulfonamides

A novel class of sulfonylurea and thiourea derivatives substituted with pyridazine and triazolopyridazine were designed and synthesized. The target compounds were assayed for their effects on the insulin release of alloxan-induced diabetic rats. The results showed that derivatives 4a, 4c, 8a, 11a, and 11b have significant antihyperglycemic effect in an experimental model of diabetes mellitus. No significant differences in cholesterol levels were observed between the diabetic group and diabetic groups that received the test compounds. However, the triglycerides level was reduced significantly by compound 8a when compared with the diabetic group.

Rational design, synthesis and 2D-QSAR study of novel vasorelaxant active benzofuran-pyridine hybrids

Reaction of 3-aryl-1-(benzofuran-2-yl)-2-propen-1-ones 3a-c with malononitrile in the presence of sufficient amount of sodium alkoxide in the corresponding alcohol proceeds in a regioselective manner to afford 2-alkoxy-4-aryl-6-(benzofuran-2-yl)-3-pyridinecarbonitriles 4-37, which also obtained by treating ylidenemalononitriles 6a-q with 2-acetylbenzofuran 1 in the presence of sufficient amount of sodium alkoxide in the corresponding alcohol. The new chemical entities showed significant vasodilation properties using isolated thoracic aortic rings of rats pre-contracted with norepinephrine hydrochloride standard technique. Compounds 11, 16, 21, 24 and 30 exhibited remarkable activity compared with amiodarone hydrochloride the reference standard used in the present study. CODESSA-Pro software was employing to obtain a statistically significant QSAR model describing the bioactivity of the newly synthesized analogs (N=31, n=5, R(2)=0.846, R(2)cvOO=0.765, R(2)cvMO=0.778, F=27.540. s(2)=0.002).