The Novel target compounds (CP-1-7) were synthesized and tested at doses up to 1000 mg/kg for their entitled activities. They exerted promising results without any behavioral changes and mortality in mice. Therefore, according to the results obtained in our study, it could be categorized as highly safe agents for treating UC since substances possessing LD50 higher than 50 mg/kg are considered nontoxic. They also possessed a potent anti-ulcerogenic activity with different potentials. The most effective compound was CP-4, it produced 97.7% ulcer protection of control followed by CP-3, which produced 90.3% protection, while the standard drug ranitidine (100 mg/kg) produced 49.2% protection. Compound CP-1 showed lowest activity among the current series, it produced 55.5% protection. The target compounds were significantly more effective than the standard in reducing ulcer index. The anti-ulcerative colitis activity was tested using acetic acid induced colitis model. The curative effect of the tested compounds at a dose of 50 mg/kg oral administration on rats showed a potent anti-ulcerative colitis activity with different potentials. They induced a significant decrease in ulcer score, ulcer area, ulcer index and weight/length of the colon specimens. The percent protection of control colitis ranged from 66.8% for CP-7 to 22.3% for CP-5; however the percent protection for dexamesathone (0.1 mg/kg) was 59.3%. The effect of the tested compounds CP-7 and CP-3 at dose 50 mg/kg were significantly more effective than dexamesathone (0.1 mg/kg) in reducing all parameters. Liver functions were not affected as there is no effect on the activity of both AST and ALT in animals that received the compounds, so the compounds didn't reveal hepatotoxic manifestation. Although, the results on kidney functions showed that, CP-1 slightly elevated blood urea concentration and CP-3 & CP-4 slightly elevated serum creatinine; no apparent nephrotoxic manifestations were recorded.
Two novel quinazoline derivatives named as; 3-[(4-hydroxy-3-methoxy-benzylidene)-amino]-2-p-tolyl-3H-quinazolin-4-one (5) and 2-p-Tolyl-3-[3,4,5-trimethoxy-benzylidene-amino]-3H-quinazolin-4-one (6) in addition to one acetamide derivative named as 2-(2-Hydroxycarbonylphenylamino)-N-(4-aminosulphonylphenyl) 11 were synthesized, and evaluated for their anti-ulcerogenic & Anti-Ulcerative colitis activities. All of the three compounds showed curative activity against acetic acid induced ulcer model at a dose of 50 mg/kg, they produced 65%, 85% & 57.74% curative ratio for compounds 5, 6 & 11 respectively. The effect of the tested compounds 5, 6 & 11 at dose 50 mg/kg were significantly (P
A novel and safe essential amino acid (Leucine) incorporating sulfanilamide was synthesized, and evaluated for its anti-ulcerogenic activity and in vitro anti-Helicobacter pylori activity. The new molecule showed a dose dependent activity against absolute ethanol-induced ulcer in rats, it produced percent protection of control ulcer by 66.7 at dose 100 mg/kg. In addition it showed a potent anti-Helicobacter pylori activity in vitro against 7 clinically isolated strains. The minimum inhibitory concentration (MIC) ranged from 12.5 to 50 μg/ml. The preliminary safety studies and toxicity profile are optimistic and encouraging.
Condensation of substituted anthranilic acids with 4-isothiocyanatoethyl-benzenesulfonamide led to series of heterocyclic benzenesulfonamides incorporating 2-mercapto-quinazolin-4-one tails. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA XII (a transmembrane, tumor-associated enzyme also involved in glaucoma-genesis). The new sulfonamides acted as medium potency inhibitors of hCA I (KIs of 28.5-2954nM), being highly effective as hCA II (KIs in the range of 0.62-12.4nM) and XII (KIs of 0.54-7.11nM) inhibitors. All substitution patterns present in these compounds (e.g., halogens, methyl and methoxy moieties, in positions 6, 7 and/or 8 of the 2-mercapto-quinazolin-4-one ring) led to highly effective hCA II/XII inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of isoforms CA II and XII is dysregulated.
A series of symmetric molecules incorporating aryl or pyridyl moieties as central core and 1,4-substituted triazoles as a side bridge was synthesised. The new compounds were investigated as lactate dehydro-genase (LDH, EC 1.1.1.27) inhibitors. The cancer associated LDHA isoform was inhibited with IC50 = 117-174 µM. Seven compounds exhibited better LDHA inhibition (IC50 117-136 µM) compared to known LDH inhibitor - galloflavin (IC50 157 µM).
Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against α-glucosidase and α-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N'-(substituted-benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a-f and 1-(substituted-phenyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a-f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b-d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited α-glucosidase (IC50 = 9.99 ± 0.18 µM); which is comparable to quercetin (IC50 = 9.93 ± 0.66 µM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against α-amylase (IC50 > 200 µM). Structure-based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as α-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications.