Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry - Volume 17, Issue 2, 2018

Serine protease, Human Neutrophil Elastase (HNE), has been shown to be useful in medical science, however, its over production and malfunctioning may produce devastating effects and cause serious damage to the host. Unfortunately, the present approved drug, sivelestat, only alleviates the symptoms of the diseases caused by malfunction of HNE but not the disease progression. Therefore, there is a crucial need to search potent and safer molecules as elastase inhibitors and to develop better anti-inflammatory drugs in future. In addition, nature is the best architect that may provide a safer future drug candidate as HNEproduction/ activity inhibitor. Since phenolic natural products are already known as antiinflammatory compounds, either by acting as antioxidants or by any other mechanism, thus, this review article summarizes the discovery and elastase inhibitory activity of ∼180 phenolics isolated from diverse natural sources during more than one decade, i.e. 2005-2017.

Background: Inhibition activity of 8 synthetic molecules known as anti-allergy drugs on lipases has been investigated. The enzymatic inhibition produced by these molecules is described here for the first time. Objective: The used anti-allergy drugs are: Loratidine, primalan, zyrtec, histagan, periactin, ketotifene, rifex and bilastine. Methods: Lipase inhibition is studied using the spectrophotometric method. Molecular docking has been achieved for the first time for these drugs using AutoDock Vina program to discuss the nature of interactions, structure-activity relationship and the mechanism of inhibition. Results: The biological evaluation of these molecules showed that most of these drugs are potent lipase inhibitors with competitive type inhibition. The best drug is loratidine with IC50=0.44mg/ml and Ki=0.86 mM and competitive type inhibition. Molecular docking studies of the studied molecules confirmed their competitive inhibitory type with their binding to the Catalytic Active Site (CAS) of lipases. Conclusion: Hence, these drugs could be used for obesity or candidiasis treatment taking advantage of the much-known details of their secondary effects as antiallergy drugs.

Background: A new series of 2-(4-acetyl-3-methyl-5-(arylamino) thiophen-2- yl)-3-arylquinazolin-4(3H)-one derivatives (11a-11j) were synthesized from acetyl acetone, phenyl isothiocyanate and 2-chloromethyl quinazolinone. Objective: Due to side effects of Non Steroidal Anti-Inflammatory Drugs (NSAID), an attempt was made to identify the novel tetrasubstituted thiophene lead compound as potential anti-inflammatory and antioxidant agent. Methods: Then newly synthesized compounds were characterized by IR spectroscopy, 1H NMR and mass spectrometry. The synthesized compounds were screened for their in vivo anti-inflammatory activity in carrageenan-induced rat hind paw edema model at dose 20mg/kg body weight using diclofenac sodium as a standard drug. The compounds were also evaluated for their in vitro DPPH free radical-scavenging activity and nitric oxide radical scavenging activity at the concentrations of 10, 20, 40, 60, 80 and 100 μg/mL using ascorbic acid as standard drug. Results: The results from carrageenan-induced rat hind paw edema showed that compounds 11e, 11f and 11b show a significant anti-inflammatory activity of 46.61%, 48.94% and 47.04 % protection respectively to inflamed paw but less than diclofenac sodium. Compounds 11h and 11e show good DPPH free radical scavenging and nitric oxide radical scavenging activity, respectively. Conclusion: From results, it was observed that highly substituted thiophene scaffold exhibits anti-inflammatory and antioxidant activity.

Background: Synthetic coumarin derivatives had attracted considerable attention for their broad spectrum of biological and pharmacological activities such as; anticoagulant, antiviral, antibacterial, antitumor and anti-inflammatory activities especially as COX inhibitors. Objective: Synthesis of some new coumarin esters using different benzoyl chloride derivatives. The benzoyl chloride derivatives were selected to have different hydrophobic groups and this aims to increase the lipophilicity of the final compounds hoping to increase the bioavailability and thus improve the anti-inflammatory activity. Methods: The reaction between compound III and different aromatic acyl chloride had resulted in a series of ester derivatives 1-9. All synthesized new compounds along with compound III as a parent compound and Celecoxib as a reference, were assessed for their antiinflammatory activity both in-vivo and in-vitro using the formalin-induced hind paw edema method and inhibition of albumin denaturation and Red Blood Cells (RBCs) membrane stabilization, respectively. Results: All synthesized new compounds 1-9 showed an improved activity compared with the parent compound III, in both in-vivo and in-vitro screening. In addition, compounds, 1, 5, 6, 7 and 8 showed significant anti-inflammatory activity compared with the standard compound Celecoxib with compound 6 has a comparable activity with Celecoxib in both invivo and in-vitro evaluation. Conclusion: The newly synthesized ester derivatives 1-9 showed an improved activity compared with the parent compound III, in both in-vivo and in-vitro screening which proved that the new ester derivatives improve the activity and/or bioavailability.

Background: There is a growing interest in the effects of probiotics for the prevention and treatment of skin diseases due to their immunomodulatory and antiinflammatory properties. Objective: To assess a mixture of five bacterial strains in the prevention of chronic skin inflammation in mice. Methods: Hairless SKH-1 mice received daily oral treatment with the probiotic mixture at the dose of 1x109 Colony-Forming Unit (CFU)/day (or vehicle) for three weeks. Chronic skin inflammation was induced by repeated applications of 12-O-tetradecanoylphorbol-13- acetate (TPA; control mice received acetone). Macroscopic and microscopic evaluations of skin lesions were performed and serum levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, IL-17, IL-22, IL-10 and IL-4 measured at the end of the study. Results: Treatment with the probiotic mixture significantly limited the induced chronic skin inflammation at both the macroscopic and microscopic levels. This limitation was consistent with downregulated levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL- 17 and IL-22) and up-regulated levels of the anti-inflammatory cytokines, IL-10 and IL-4. Conclusion: The results suggest that the probiotic mixture tested could help in preserving skin integrity and homeostasis and that its use could be beneficial in dermatological conditions such as atopic dermatitis and psoriasis.