Synthesis and reactions of some pyridopyrimidine and thienopyridine derivatives for antiviral evaluation

Compounds 6-amino-4-[4-chlorophenyl]-2-thien-2-ylpyridine5-carbonitrile [2] and 4-[4-chlorophenyl]-6-thioxo-2-thien-2-yll,6-dihydropyridine-5-carbonitrile [9] were prepaied using 3-[4-chlorophenyl]-l-thien-2-ylpropenone [I] and malononitrile or cyanothioacetamide, respectively. Pyridine derivative 2 was in turn used as a precursor for preparation of some pyridopyrimidine and fused pyridopyrimidine derivatives 3-8. On the other hand, the pyridine derivative 9 was used in preparation of thienopyridine derivatives 10 and 11. Moreover, fusion of compound 11 with excess of benzoyl chloride ' afforded 4-[4-chlorophenyl]-2-phenyl-7-thien-2-yl-3H-pyrido [3,2:4,5] thieno[3,2-d] pyrimidin-4-one [12]

protective effect of nigella sativa oil and the derived thymoquinone and nigellone against thioacetamide induced liver fibrosis in rats

The present study examined the effect of oral administration of Nigella saliva oil [NSO], thymoquinone [TQ], the main active principle of the volatile oil of NSO and nigellone [NG], the less toxic carbonyl polymer of TQ, on progress of thioacetamide [TAA] -induced liver fibrosis in rats. Sixty male albino rats weighing 150-200 g/rat were classified into 6 groups as follows: group I, [saline-control], group II [TAA-induced liver injury], group III [NSO-treated], group IV [TQ-treated], group V [NG-treated] and group VI [propylene glycol - treated]. NSO, TQ, NG and propylene glycol were given daily orally for 6 weeks starting with TAA administration. Propylene glycol was the vehicle of TQ and NG. TAA-injury [group II] caused a significant rise in the portal pressure and serum concentrations of tumor necrosis factor -alpha, transforming growth factor - beta[1] and malondialdehyde. Moreover, liver function tests [serum aspartate and alanine aminotransferases, alkaline phosphatase and gamma-glutamyl transferase activities and serum albumin concentration] were significantly impaired in group II as compared to group I. Liver tissues obtained from rats treated by TAA had higher hydroxyproline and lower reduced glutathione contents as compared to saline-control [group I]. Administration NSO, TQ or NG caused significant and similar protective effects against all TAA-induced haemodynamic and biochemical impairments. This study suggests that NSO, TQ and NG are significantly and probably equally effective against TAA-induced liver injury and fibrosis. Inhibition of synthesis and/or release of TNF-alpha and TGF-beta[1] as well as inhibition of tissue oxidative stress may be of particular importance

effect of inhibition of renin-angiotensin system and platelet aggregation on cholinergic responses of gastric fundus smooth muscles of streptozotocin-induced diabetic rats

Gastroparesis is the one of debilitating complications of diabetic gastrointestinal autonomic neuropathy. In the streptozotocin [STZ] induced diabetic rats, degeneration of cholinergic nerves occur. Several investigators have reported the importance of vascular factor and increased platelets activation in the pathogenesis of diabetic neuropathy. Study of the effect of an angiotensin converting enzyme inhibitor [captopril], an antiplatelet [clopidogrel] and/or insulin on autonomic neuropathy in STZ induced diabetic rats. Male albino rats were used. Diabetes was induced by a single intrapertioneal injection of STZ [75mg/kg b.wt.]. The response of rat gastric fundus smooth muscles to carbachol was considered in present study as a tool to study the cholinergic innervation of the stomach. The studied biochemical parameters were serum glucose level and glycosylated hemoglobin%[HbAlc%]. Diabetic rats showed a significant increase in serum glucose concentration and HbAlc% as compared to normal rats. Administration of insulin to diabetic rats decreased serum glucose and HbAlc% significantly as compared to diabetic non treated rats. The isolated fundus strips obtained from diabetic rats showed a significant increase in maximal response to carbachol [E[max]] and a significant decrease in concentration of carbachol required to elicit 50% of the maximal contraction response [EC[50]] as compared to normal rats. Administration of insulin to diabetic rats produced a significant decrease in E[max] and a significant increase in EC[50] as compared to diabetic rats. Diabetic rats treated by both captopril and insulin showed a significant decrease in E[max] and a significant increase EC[50] as compared to diabetic rats treated with insulin alone. The STZ -induced diabetic rats showed an alteration in the fundus strips responses to the musacrinic agonist. Treatment with insulin partly reversed or prevented this abnormality. Angiotensin II seem to be involved in the pathogenesis of diabetic cholinergic neuropathy. This was concluded from the present data which showed that the responses of rat fundal strips to carbachol could be brought to control value by combined treatment of captopril and insulin

possible renoprotective effect of angiotensin converting enzyme inhibitors and statins on renal ischemia reperfusion injury in rats

Ischemia-reperfusion-induced renal injury is the most common cause of acute renal failure [ARF]. Angiogenesis is an important phenomenon associated with recovery from ischemia. The aim of the present study was to assess the possible renoprotective effect of manipulating angiogenesis by trandolapril [an angiotensin converting enzyme [ACE] inhibitor] and simvastatin [a 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor] in ischemic ARF in rat. The present study was conducted on 40 male albino rats that were divided into four groups. Group I included normal Sham-operated rats that served as control for group II, Group II were rats in which renal ischemia reperfusion injury [RIRI] was induced and Group III and Group IV consisted of rats that received trandolapril and simvastatin respectively, orally daily starting two days before and continuing for two days after the induction of RIRI. At the end of the experimental period, serum urea and creatinine concentrations and creatinine clearance were assessed. Moreover, serum and renal vascular endothelial growth factor [VEGF] levels, renal caspase-3 activity [as an index of apoptosis], renal hemoglobin content [as an index of angiogenesis] and renal oxidative stress parameters [malondialdhyde [MDA] and reduced glutathione [GSH] concentrations] were assessed. A significant increase in serum urea, creatinine concentrations and in renal VEGF, MDA concentrations and caspase-3 activity together with a significant decrease in creatinine clearance and renal GSH concentration has been observed in non-treated rats killed two days after RIRI compared to Sham-operated rats. Administration of trandolapril or simvastatin resulted in a significant decrease in serum urea and creatinine concentrations and in renal caspase-3 activity and renal MDA concentration as well as a significant increase in creatinine clearance and renal hemoglobin and GSH concentrations in rats killed two days following RIRI compared to non-treated rats with RIRI. A significant increase in renal VEGF concentration could be observed in simvastatin-, but not in trandolapril-treated rats killed two days following RIRI compared to non-treated rats with RIRI. The present study demonstrated the proangiogenic effect and the possible renoprotective role of trandolapril and simvastatin in rats with RIRI. It has been found that the proangiogenic effect of trandolapril is independent of VEGF, while that of simvastatin might involve several factors including VEGF

study of the effect of rosiglitazone, fenofibrate and simvastatin on trinitrobenzenesulphonic acid-induced colitis in rats

Inflammatory bowel disease [IBD] is a chronic inflammatory disease involving all or a portion of the colon. The mechanism responsible for development of IBD has been mainly attributed to up-regulated inflammatory processes. Peroxisome proliferator-activated receptors [PPAR] agonists have been shown to inhibit multiple steps in the nuclear factor [NF] kappa B signaling pathway resulting in suppression of inflammation. The aim of the present study was to investigate the effect of rosiglitazone, fenofibrate and simvastatin on an animal model of ulcerative colitis. The study was carried out on 72 adult male albino rats. Colitis was induced by intracolonic instillation of trinitrobenzenesulfonic acid [TNBS]. The severity of inflammation was assessed by measurement of ulcer index score,colonic weight /length ratio, colonic tissue myeloperoxidase enzyme activity, colonic tissue tumor necrosis factor alpha [TNF-alpha] content. The inflammation -induced oxidative stress was also assessed by measurement of colonic tissue contents of malondialdehyde and reduced glutathione. In the present study, intracolonic instillation of TNBS to rats produced a significant inflammation Sulfasalazine, rosiglitazone, and simvastatin- treated groups showed a significant reduction in the inflammatory process and oxidative stress parameters. The fenofibrate-treated group showed only a significant reduction in the inflammatory process parameters. When compared to sulfasalazine treated group, all the single drug treated groups showed significant differences in the all measured parameters. Combined rosiglitazone - simavastatin, and fenofibrate + simavastatin treated groups showed an insignificant difference in the inflammatory and oxidative stress parameters as compared to sulfasalazine treated group. Based on the results of the present study, it can be concluded that rosiglitazone, fenofibrate and simvastation conferred a good anti-inflammatory activity against TNBS induced-colitis in rats. Their mechanism of action involves the decrease in inflammatory cell infiltration, TNF-alpha concentration and oxidative stress Nevertheless, these drugs when used as monotherapy were not efficient as compared to sulfasalazine. However, simvastatin can act synergistically with either rosiglitazone or fenofibrate to produce very effective anti-inflammatory effects against colitis. Clinical trials are required in the future in order to evaluate the effect of these potential anti-inflammatory drugs in patients with IBD