Samia G. Abdel-Moty

Synthesis and anti-inflammatory testing of some new compounds incorporating 5-aminosalicylic acid (5-ASA) as potential prodrugs.

This work includes the synthesis of 15 final compounds (6a-h and7b-h) as prodrugs of 5-ASA in the form of the acid itself, esters and amides linked by an amide linkage through a spacer to the endocyclic ring N of nicotinamide. Also, 15 new intermediate compounds were prepared. The target compounds (6b, 6f, 7b, and7e-h) revealed potent analgesic and anti-inflammatory activities in comparison to sulfasalazine and 5-ASA. In addition, ulcerogenicity, LD50,in vivo andin vitro metabolism of compound7f were determined.

5-Aminosalyclic Acid (5-ASA): A Unique Anti-Inflammatory Salicylate

Salicylic acid (SA) derivatives are widely used for treatment of various diseases. Acetylsalicylic acid represents the most widely used drug in the world, 4-Aminosalicylic acid (4-ASA) was historically used as a systemic antituberculosis drug as well as diflunisal is a strong pain killer and antipyretic. 5-Aminosalicylic acid (5-ASA) which had been synthesized at the end of 19th century and employed first for the production of azo dyes, was then identified as a very valuable medicinal agent as well as part of many biologically active agents. 5-ASA is not metabolized to salicylic acid for pharmacological activity. It is not considered a true salicylate. In contrary to other salicylates, 5-ASA doesn’t induce upper gastrointestinal (GI) side effects. Moreover, It was found, especially, useful for treatment of inflammatory bowel diseases (IBD). It is unique among salicylates and has a broad specrum of biological activities including, anti-inflammatory, analgesic, neuroprotective and antitumor. Since we are interested in this compound and its derivatives, we prepared this review to give insight into its chemistry, anti-inflammatory activity, in particular, for treatment of IBD. Different approaches for colonic targeting of 5-ASA w ill be covered with emphasis on chemical methods as well as its proposed mechanisms of action.

Synthesis of new 4,5-3(2H)pyridazinone derivatives and their cardiotonic, hypotensive, and platelet aggregation inhibition activities

Abstract4,5-dihydro-3(2H)pyridazinones such as CI-914, CI-930 and pimobendan along with tetrahydropyridopyridazine (endralazine) and perhydropyridazinodiazepine (cilazopril) have been used as potent positive inotropes, antihypertensives as well as platelet aggregation inhibitors. Accordingly, the present work involves the synthesis of 24 target compounds; 4,5-dihydro-3(2H)pyridazinones in addition to seven reported intermediates. The chemical structures of the new compounds were assigned by microanalysis, IR, 1H-NMR spectral analysis and some representatives by mass spectrometry. The positive inotropic effect of the final compounds and the intermediates 12a–12d as well as the reported intermediate compound 10 was determined in-vitro on isolated rabbit heart in comparison to digoxin. Data obtained revealed that twelve of the test compounds exhibited higher effective response than digoxin, nine compounds elicited comparable effects to digoxin and eight compounds were less active than digoxin. In addition, four compounds approved marked significant hypotensive effect better than that of the previously reported compound 10. Moreover, two compounds induced complete platelet aggregation inhibition. The last two compounds were also subjected to determination of their LD50 and they showed no signs of toxicity up to the dose level 300 mg/kg (i.p.), while the reported oral LD50 of digoxin is 17.78 mg/kg. Correlation of cardiotonic and hypotensive activities with structures of compounds was tried and pharmacophore models were computed to get useful insight onto the essential structural features required for inhibiting phosphodiesterase-III in the heart muscles and blood vessels.

Design and synthesis of novel 5-aminosalicylate (5-ASA)-4-thiazolinone hybrid derivatives with promising antiproliferative activity.

Two privileged pharmacophores were assembled in one molecular frame involving 5-aminosalicylate and 4-thiazolinones that can be found in different stereochemical features. The compounds were fully characterized and evaluated for antiproliferative activity against four human cancer cell lines and some are equipotent to doxorubicin with lower cytotoxicity to normal cells. The most interesting finding relates to compound 10, which shows an IC50 value of 70nM against MCF-7 cells, while the IC50 against human fibroblasts is 10μM. The results of this study indicate that the new compounds are optimal anti-cancer leading compounds and merit further studies to optimize their structure, detect their biotargets and in vivo activity.

Synthesis, biological evaluation and docking study of 1,3,4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX

Selective inhibition of both cyclooxygenase-2 (COX-2) and 15-lipooxygenase (15-LOX) may provide good strategy for alleviation of inflammatory disorders while minimizing side effects associated with current anti-inflammatory drugs. The present study describes the synthesis, full characterization and biological evaluation of a series of thiadiazole-thiazolidinone hybrids bearing 5-alk/arylidene as dual inhibitors of these enzymes. Our design was based on merging pharmacophores that exhibit portent anti-inflammatory activities in one molecular frame. 5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-amine (3) was efficiently synthesized, chloroacetylated and cyclized to give the key 4-thiazolidinone (5). Knovenagel condensation of 5 with different aldehydes afforded the final compounds 6a-m, 7, 8 and 9. These compounds were subjected to in vitro COX-1/COX-2, 15-LOX inhibition assays. Compounds (6a, 6f, 6i, 6l, 6m and 9) with promising potency (IC50 = 70-100 nM) and selectivity index (SI = 220-55) were further tested for in vivo anti-inflammatory activity and effect on gastric mucosa. The most promising compound (6l) inhibits COX-2 enzyme at a nanomolar concentration (IC50 = 70 nM, SI = 220) with simultaneous inhibition of 15-LOX (IC50 = 11 µM). These results are comparable to the potency and selectivity of the standard drugs of both enzymes; celecoxib (COX-2 IC50 = 49 nM, SI = 308) and zileuton (15-LOX IC50 = 15 µM) in one construct. Interestingly three compounds (6a, 6l and 9) exhibited equivalent to or even higher than that of celecoxib in vivo anti-inflammatory activity at 3 h interval with good GIT safety profile. Molecular docking study conferred binding sites of these compounds on COX-2 and 15-LOX. Such type of compounds would represent valuable leads for further investigation and derivatization.