Zuhair Muhi-eldeen

Anti-inflammatory aminoacetylenic isoindoline-1,3-dione derivatives modulate cytokines production from different spleen cell populations.

We recently designed a series of N-[4-(t-amino-yl)-but-2-yn-1-yl] isoindoline-1,3-diones as anti-inflammatory compounds, called ZM compounds. These ZM compounds were categorized according to the nature of the cyclic amino groups into ZM2, ZM3, ZM4, and ZM5 and were shown to reduce carrageenan-induced inflammation, inhibit cyclooxygenase (1 and 2) and have less adverse effects than the common non-steroidal anti-inflammatory drugs. In the present study, we are examining the potential effects of ZM compounds in modulating cytokines production in vivo and in vitro from stimulated spleen cells, CD4+ CD25+ve T regulatory cells and CD4+CD25-ve T helper cells. Six hours following oral administration of 20mg/kg of ZM4 and ZM5 compounds reversed LPS-induced TGF-β suppression whereas ZM2, ZM3, ZM4, and ZM5 reversed LPS-induced TNF-α and IL-12 increase in mice spleen. In addition, increasing concentrations of ZM2, ZM4 and ZM5 increased significantly TGF-β1 production, whereas ZM3, ZM4 and ZM5 suppressed only TNF-α production in LPS and LPS+PMA stimulated spleen cells. Furthermore, only ZM5, enhanced significantly TGF-β1 production from LPS and LPS+PMA stimulated CD4+CD25+ve cells (p<0.001), whereas none of the ZM compounds modulated TNF-α from CD4+CD25-ve T helper cells. These results indicate that ZM5 (N-{4-(2-Azepan-1-yl)-but-2-yn-1-yl}isoindoline-1,3-dione) enhances TGF-β production from CD4+CD25+ve cells independent of protein kinase C activation and suggest that all ZM compounds suppress TNF-α from monocytes/macrophage cells. In conclusion, these ZM compounds have potential to be used use as anti-inflammatory agents and further studies to show the possibility of utilizing these basic aminoacetylenic isoindolines in autoimmune mediated inflammatory diseases are warranted.

Analgesic and Toxicity Studies of Aminoacetylenic Isoindoline-1,3-dione Derivatives

We have developed a series of aminoacetylenic isoindoline-1,3-dione compounds and showed their anti-inflammatory activities by reducing carrageenan-induced rat paw edema and modulating proinflammatory and anti-inflammatory cytokines. In the present study and due to efficacy reasons, we are exploring only two of these compounds, namely, ZM4 and ZM5, to reveal their analgesic activity and toxicity. Following oral administration, both compounds were effective in reducing significantly (P < 0.05–0.001) acetic acid-induced writhing behavior, hot plate latency test, and formalin-induced paw licking time as antinociceptive indicators in mice and rats, respectively. Regarding the toxicity, the acute (20, 50, and 150 mg/kg) and repeated oral administration (10, 20, and 50 mg/kg) of these compounds for ten days did not produce any mortality and the compounds were considered well tolerated. However, repeated oral administration of 50 mg/kg of both compounds induced erythropoiesis by means of increasing significantly red blood cells, hemoglobin, and packed cell volume. Moreover, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic and anti-inflammatory activity compared to indomethacin as a positive control. The results indicate that ZM4 and ZM5 possess potential analgesic activity while being preliminarily safe and have minimal ulcerogenic activity.

Non-Selective Inhibition of Cyclooxygenase Enzymes by Aminoacetylenic Isoindoline 1,3-Diones

The reported pharmacological activities of acetylenic and phthalimide groups promoted our interest to synthesize a novel series of N-[4-(t-amino-yl)-but-2-yn-1-yl] isoindoline-1,3-diones as anti-inflammatory compounds. The aim of this research is to investigate the selectivity of two compounds, ZM4 and ZM5, on inhibiting cyclooxygenase (COX) in vitro and in silico as well as reducing carrageenan-induced edema in rats. Oral administration of 5-20 mg/kg ZM4 and ZM5 reduced significantly carrageenan-induced edema in dose-and time dependent manner. Furthermore, the IC50 values induced by ZM4 and ZM5 were in the range of 3.0-3.6 μM for COX1 and COX 2 but were higher than those induced by Diclofenac and Celecoxib, respectively. Docking of ZM4 and ZM5 in both COX enzymes, on the other hand, exhibited the conventional binding modes that are usually adopted by different non-steroidal anti-inflammatory drugs (NSAIDs). Furthermore, ZM4 and ZM5 bind to COX enzymes as strongly as Flurbiprofen and Celecoxib. In conclusion, aminoacetylenic isoindoline 1, 3-dione compounds have shown anti-inflammatory activity by inhibiting COX-1 and COX-2 enzymes. Interestingly, the best hits showed inhibition at low micromolar levels although they are not selective at this stage. Further research will be conducted to improve both selectivity and potency.

Synthesis and biological evaluation of N1,N2-bis-[4-(t-amino)-2-butynyl]phthalamides as oxotremorine and acetylcholine antagonists

A series of N1,N2-bis-[4-(t-amino)-2-butynyl]phthalamides have been synthesized and investigated for the blocking of the motor effect of oxotremorine in intact mice and for their antagonistic activity towards acetylcholine on isolated guinea pig ileum preparations. All N1,N2-bis-[4-(t-amino)-2-butynyl]phthalamides showed more selectivity as oxotremorine antagonists than atropine and less potent than atropine on peripheral cholinergic antagonistic activity.

ACETYLENIC DIMERIZATION UNDER BASIC CONDITIONS

Objective: Cerebrovascular accident (CVA), formally called as stroke is the second leading cause of death worldwide. Recent studies in different parts of India also documented that the prevalence of stroke varies from 40 to 270 per 100,000 populations. Identifying the risk factors of the disease helps to improve the effectiveness of the therapy. Our present study aims in accessing the risk aspects and utilization of drugs in CVA patients. Methods: A prospective Interventional study was carried out on stroke patients in Medicine Department, Viswabarathi Hospital, Kurnool, AP from January to September 2015. Required demographic and laboratory data, along with general neurological evaluation and brain CT was analyzed. Results: A total of 100 patients was analyzed. Among them, the incidence of ischemic stroke (96%) was greater compared to hemorrhagic stroke (4%). Prevalence of disease was higher in males (69%) than females (31%) with notable occurrence in the age group of 61-70 (26%). Higher percentage of patients were found to have>3 risk factors (34%), including hypertension (68%), age (58%), diabetes (39%), smoking (22%), alcoholism (21%), CAD (10%) and percentage with no risk element accounts7%. The prescribing pattern includes antihypertensives (16.25%), Gastrointestinal agents (12.2%), anti-platelets (9.16%), hyperlipidemic (8.4%), Nootropics (7.97%) followed by other classes and nitrates (0.62%) occupies the last place in prescribing. Conclusion: The present study emphasizes on the need to identify risk factors and providing awareness among the patients by a pharmacist in minimizing the disease burden. It also points the rationality in prescribing of drugs based on therapeutic guidelines.

Synthesis of 2-[{4-(t-amino-1-yl) but-2-yn-1-yl }oxy]-1,3- benzothiazole derivatives as H3-antagonists

Aminoacetylenicoxybenzothiazole derivatives were synthesized from the reaction of 2hydroxybenzothiazole with 3-bromoprop-1-yne to generate 2-(prop-2-ynl-1-yloxy)-1,3-benzothiazole (RM-1). A mixture of 2-(prop-2-yn-1-yloxy)-1,3-benzothiazole, paraformaldehyde, cyclic amine and cuprous chloride catalytic amount, in peroxide-free dioxane through Mannich reaction yielded the desired aminoacetylenicoxybenzothiazoles (RM2-7). The mp, IR, 1H-NMR, C-NMR and elemental analysis were consistent with the assigned structures. The design of these compounds as H3 antagonists was based on the rationalization for the important criteria needed to overlap effectively with H3 receptor to induce antagonistic activity. These criteria are: 1) The basic amino group for ionic binding. 2) The acetylenic group for electrostatic interaction. 3) The 2-butyne provide the appropriate distance between the basic nitrogen and benzthiazole. 4) Oxy ether to provide hydrogen bonding with H3 receptor and 5) benzothiazole group found in H3 antagonists and many other biologically active compounds. The docking results showed that all the designed compounds have a good H3 receptor antagonism especially RM-7 which have -6 (kcal/mol). These results provide a good lead to design more effective H3 antagonists in managing Alzheimers and other diseases like depression, epilepsy, schizophrenia and many other CNS disorders.

Synthesis and pharmacological evaluation of N-(4-(t-amino)-2- butynyloxy) phthalimides

A series of aminoacetylenicoxyphthalimide namely N-(4-(t-amino)-2-butynyloxy) phthalimides were synthesized from the reaction of N-hydroxyphthalimide with propargyl bromide in sodium ethoxide to generate N-(2-butynyloxy)phthalimide. The desired compounds were prepared through Mannich reaction of N-(2-butynyloxy)phthalimide with formaldehyde, appropriate amine in peroxide-free dioxin and cuprous chloride as catalyst. The N-(4-(t-amino)-2-butynyloxy) phthalimides were investigated for their rectal temperature, motor activity and palpebral pitosis effects in comparison with harmaline, all compounds showed similar activity to harmaline, however compound 4 was more potent than harmaline.