Dalia O. Saleh

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.

Modulatory role of Co-enzyme Q10 on methionine and choline deficient diet-induced non-alcoholic steatohepatitis (NASH) in albino rats

The present study aimed to evaluate the hepato-protective and neuro-protective activity of Co-enzyme Q10 (CoQ10) on non-alcoholic steatohepatitis (NASH) in albino rats induced by methionine and choline-deficient (MCD) diet. Rats were fed an MCD diet for 8 weeks to induce non-alcoholic steatohepatitis. CoQ10 (10 mg/(kg·day)-1) was orally administered for 2 consecutive weeks. Twenty-four hours after the last dose of the drug, the behavioral test, namely the activity cage test, was performed and the activity counts were recorded. Serum alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, total/direct bilirubin, and albumin were valued to assess liver function. Moreover, hepatic cytokines interleukin-6 as well as its modulator nuclear factor kappa-light-chain-enhancer of activated B cells were determined. In addition, brain biomarkers, viz ammonia, nitric oxide, and brain-derived neurotrophic factor (BDNF), were measured as they are reliable indices to assess brain damage. Histopathological and immunohistochemical examination of brain proliferating cell nuclear antigen in brain and liver tissues were also evaluated. Results revealed that MCD-induced NASH showed impairment in the liver functions with an increase in the liver inflammatory markers. Moreover, NASH resulted in pronounced brain dysfunction as evidenced by hyper-locomotor activity, a decrease in the BDNF level, as well as an increase in the brain nitric oxide and ammonia contents. Oral treatment of MCD-diet-fed rats with CoQ10 for 14 days showed a marked improvement in all the assigned parameters. Finally, it can be concluded that CoQ10 has a hepatoprotective and neuroprotective role in MCD-diet-induced NASH in rats.

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.

Trigonelline attenuates hepatic complications and molecular alterations in high-fat high-fructose diet-induced insulin resistance in rats

The present study aimed to evaluate the effect of trigonelline (TRG) on the hepatic complications associated with high-fat high-fructose (HFHF) diet-induced insulin resistance (IR) in rats. IR was induced by giving a saturated fat diet and 10% fructose in drinking water to rats for 8 weeks. Insulin-resistant rats were orally treated with TRG (50 and 100 mg/kg), sitagliptin (SIT; 5 mg/kg), or a combination of TRG (50 mg/kg) and SIT (5 mg/kg) for 14 days. Liver homogenates were used for assessment of hepatic lipids, oxidative stress biomarkers, and inflammatory cytokines. Histopathological and DNA cytometry examinations were carried out for hepatic and pancreatic tissues. Hepatic tissues were examined using Fourier-transform infrared spectroscopy for assessment of any molecular changes. Results of the present study revealed that oral treatment of insulin-resistant rats with TRG or TRG in combination with SIT significantly decreased homeostatic model assessment of IR, hepatic lipids, oxidative stress biomarkers, and the inflammatory cytokines. TRG or TRG in combination with SIT ameliorated the histopathological, DNA cytometry, and molecular alterations induced by a HFHF diet. Finally, it can be concluded that TRG has beneficial effects on the hepatic complications associated with IR due to its hypoglycemic effect and antioxidant potential.

Hypoglycemic activity of Gleditsia caspica extract and its saponin-containing fraction in streptozotocin-induced diabetic rats.

Abstract The fruits of Gleditsia species (Fabaceae) have been known in traditional medicine as a saponin-rich herbal medicine. The present study aimed to investigate the effects of the total methanolic extract of Gleditsia caspica (MEGC) and its saponin-containing fractions (SFGC) on hyperglycemia in streptozotocin (STZ)-induced diabetic rats. A single intraperitoneal injection of STZ (55 mg/kg body weight) was used to induce hyperglycemia in male albino rats. MEGC (15, 30 and 60 mg/kg, p.o.) and SFGC (15, 30 and 60 mg/kg, p.o.) were administered to the diabetic rats daily for 14 days. The anti-diabetic drug gliclazide (10 mg/kg, p.o.) was used as a positive control. Blood samples were collected from overnight fasted rats for the evaluation of the antihyperglycemic, antihyperlipidemic and antioxidant activities. The levels of glucose, triglycerides (TG), cholesterol (TC) and malondialdehyde (MDA) were increased significantly, whereas the levels of α-amylase, insulin and reduced glutathione (GSH) were decreased in the experimental diabetic rats. Pancreas and liver of the diabetic rats exhibited significant changes in the histopathology, morphology and DNA content. Administration of MEGC or SFGC led to a decrease in the levels of glucose, TG, TC and MDA. In addition, the levels of α-amylase, insulin and GSH were increased in MEGC and SFGC treated diabetic rats. Also, the histopathological and morphological changes, as well the changes in DNA were significantly reversed by the extracts. Thus, MEGC and SFGC exhibited potent hypoglycemic and hypolipidemic activities in STZ- induced diabetic rats.

Synthesis, Evaluation of Pharmacological Activity, and Molecular Docking of 1,4-Dihydropyridines as Calcium Antagonists

1,4-Dihydropyridine (DHP) is an important class of calcium antagonist. It inhibits the influx of extracellular Ca(2+) through L-type voltage-dependent calcium channels. Two series of nifedipine analogues were synthesized and evaluated as calcium antagonists. The ortho-nitrophenyl ring of nifedipine was replaced with an ortho- or a meta-chlorophenyl substituent. The IC50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution with groups of suitable bulkiness, such as ethyl ester, at the 3- and 5-positions of the DHP ring gave 3h, which is approximately three-fold more active than nifedipine as a calcium antagonist. A docking study with the DHP receptor model was performed to interpret the differences in calcium antagonist activities. The molecular docking study demonstrated that the lipophilicity of the substituted phenyl group at the 4-position of the DHP ring is an important factor that could increase the activity of the calcium antagonist taking the steric factor into consideration. Bulky groups interfere with ring-to-ring hydrophobic interaction with Tyr(1460) and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3- and 5-positions of the DHP ring as an approach to increase activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring may ensure strong binding to the receptor and hence stabilization of the closed-channel conformation.

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).