Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 14, Issue 3, 2015

Background: Inflammation is a natural reaction of our body in response to infection or any other injury to renovate that damage. The majority of the available Non-steroidal anti-inflammatory drugs is nonselective and consequently, causes gastric irritation and ulceration. Therefore, it is a beard to design and synthesize a new series of Non-steroidal anti-inflammatory drugs with minimal gastric complications. Methods: A series of novel 4-(3,4-dimethylphenyl)-2(1H)-phthalazinone derivatives were designed, synthesized and evaluated for their in vivo anti-inflammatory activity. The compounds that showed powerful anti-inflammatory activities were assessed for their in vitro COX-1/COX-2 inhibitory activity and their in vivo ulcerogenic profile. The interaction between the designated compounds and the binding pocket of the COX-2 enzyme was predicted by molecular docking stimulation. Results: Six compounds, 2, 4, 5, 7a, 7b, and 8b showed significant anti-inflammatory activities at 4h compared to standard drug celecoxib. Compounds 4, 5, and 8b were the most potent and selective COX-2 inhibitors. Moreover, all the screened compounds demonstrated higher gastric safety profile compared to celecoxib particularly compound 8b displayed the highest safety profile. Among the tested compounds, 8b displayed the best fitting score, the highest antiinflammatory activity and COX-2 selectivity with minimal ulcer score. Conclusion: A new series of phthalazinone derivatives were successfully synthesized and were evaluated for their in vivo anti-inflammatory activity. Six compounds (2, 4, 5, 7a, 7b, and 8b) presented powerful anti-inflammatory activity compared to celecoxib. Moreover, compounds 4, 5 and 8b were the most potent inhibitors to COX-2 and were inactive to COX-1. The screened compounds showed better ulcer protection and less gastric lesion compared to celecoxib. Compound 8b was the most promising candidate with more gastric safety.

Background: Matrix metalloproteinases (MMPs) contribute to various physiological and pathophysiological processes. An imbalance in MMP activity causes pathological conditions including inflammatory diseases, cancer, and cardiovascular diseases. Each MMP member has many 3D structures available; therefore, selecting one structure for virtual screening becomes challenging. Methods: In this study, we used the cross-docking approach to rank the available MMP structures for their probable successful performance in virtual screening. To determine structures that would offer best average RMSD (root mean square deviation), we performed cross-docking studies on 123 holo (protein–ligand) structures of seven MMP enzyme groups (MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13). Results: MMP enzymes with more flexible residues had fewer structures with RMSD < 2.0 A. Further, same resolution and binding affinities, difference in ligand size, and chemotype of the co-crystalized ligand were parameters that could greatly affect the corresponding cross-dock results and the calculated average RMSD for the structures. Four of the six best MMP-12 receptors, which were identified using the average RMSD metric, had the highest EF1% (emrichment factor) in the retrospective enrichment study. Conclusion: According to the enrichment results, structures with lower average RMSD have a high probability of being appropriate candidates. These study findings will help in receptor selection for an MMP virtual screening protocol and lead to better enrichment of MMP inhibitors.

Background: Oxygen has double-edge properties as it is essential for life, but can also provoke oxidative stress by protein & lipid per oxidation. The persistent oxidative stress and excess LPO induce several inflammatory mediators such as prostaglandins and leuckotrienes by activating enzymes cyclooxygenase and lipoxygenase. The per oxidation can be blocked by free radical scavengers as antiinflammatory agents. Most of the anti-inflammatory agents, which inhibit the above mentioned enzymes, are associated with side effects such as ulceration and bleeding in gastrointestinal tract; so the attention is focused on benzylideneacetophenones having antinflammatory, antioxidant and gastric protectant activities by virtue of free radical scavengers. A systematic analysis of the structural features responsible for biological activities and a possible mode of their actions were proposed to be evaluated by synthesizing a set of compounds, screening them for anti-inflammatory, antioxidant and antiulcer activity. Methods: The benzylideneacetophenones derivatives were synthesized employing the Claisen-Schmidt condensation. The structure of the compounds were established by IR, 1H NMR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory (carrageenan-induced rat paw edema assay), antioxidant (inhibition of lipid peroxidation) and antiulcer activity (indomethacin-induced gastric damage). Possible correlation between observed biological activities and substituents at different positions on rings was also studied. Results: The data revealed that compounds 1e, 1m and 1l showed equivalent activity to indomethacin (reference drug) at the fourth hour at dose of 100 mg/kg. Among the tested compounds 1m & 1l exhibited the highest lipid per oxidation inhibitory activity (IC50 2.38μg/ml, 3.08 μg/ml) followed by 1i, 1h, 1e. In addition, all compounds at the tested dose level (100mg/kg, p.o.) exhibited varying degree of activity against ulceration induced by indomethacin. The compounds 1m, 1l, 1e, and 1i showed excellent activity (71-75%), whereas compounds 1d, 1h and 1j exhibited good to moderate (60-69%) activity. SAR analysis revealed that presence of electron donating groups on p- position of both rings A and B seems to enhance anti-inflammatory, antioxidant and antiulcer activity. Conclusion: The compound 1m (4-amino-4’-ethoxychalcone) and 1l (4-amino-4’-methoxychalcone) have equivalent antiinflammatory activity in comparison with the reference drug. Moreover, the same compounds also obtained promising antioxidant and antiulcer activities. Thus, I m could be explored further for development of potent anti inflammatory agent.

Background: 3,4-dihydroxycinnamic acid and its derivatives exhibit numerous biologic activities. Such activities have not previously been reported for 3,5-dihydroxycinnamic acid derivatives. In this study, ten derivatives of 3,5- dihydroxycinnamic acid were synthesized and their anti-inflammatory activities were tested in 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema. Molecular biological studies have shed lights on their anti-inflammatory mechanism. Methods: Anti-inflammatory activities of ten new synthesized derivatives of 3,5-dihydroxycinnamic acid were tested in 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema, and their anti-inflammatory mechanism was studied by ELISA, real-time RT-PCR, MPO assay and AA-induced mouse ear edema. Results: Compound 7 showed a pronounced anti-inflammatory effect and the inhibition rate was 65.6% at a dose of 1.6mg/ear. This compound acted by reducing mRNA and protein synthesis of tumor necrosis factor-α, interleukins 1β and 6, and also by decreasing the levels of activated neutrophil infiltrates. Furthermore, compound 7 significantly suppressed arachidonic acid-induced edema as well. Cell-based assays showed that compound 7 inhibited the production of cyclooxygenase- 2-catalyzed prostaglandin E2 from lipopolysaccharide-treated RAW 264.7 cells, and also inhibited 5-lipoxygenase production from A23187-treated RBL-1 cells, and consequently reduced leukotriene B4 production. Conclusion: This investigation revealed that some of the derivatives of 3,5-dihydroxycinnamic acid exhibit a more pronounced anti-inflammatory effect than 3,4-dihydroxycinnamic acid. Therefore, 3,5-dihydroxycinnamic acid derivatives, especially compound 7, represent potential value for antiinflammatory drug development.

Objective: To compare the ratings given by the caregivers regarding the health status of their rheumatoid arthritis (RA) patients to those recorded by the patients themselves and to assess the effect of caring for a patient with RA on the mental health of the caregiver. Methods: This is a non-interventional, cross-sectional, multi-center epidemiological study conducted at the outpatient clinics of two hospitals in Saudi Arabia. The patients included were diagnosed with RA, over 18 years of age with 1-5 years of disease duration, and all had an identifiable single caregiver who was willing to participate in the study. Results: 40 patients of whom 92.5% were women and the mean age of 44.6 years. The mean visual analogue scale (VAS) score was 4.98 for general health. The mean Health Assessment Questionnaire (HAQ) for the patients according to themselves was 1.31 (±0.68), while that stated by caregivers was 1.40 (±0.69); thus, the mean scores given by the caregivers was 0.091 points higher than that provided by the patients themselves (95% confidence interval [CI], 0.167–0.014) (p=0.0214). Further, 43% of the caregivers gave higher HAQ scores to their related patients than the patients themselves, while 30% gave similar HAQ scores. The caregivers scored a mean of 21 points in the Zarit Burden Interview (±12.1), with 47.5% reporting mild to moderate burden, and 5% reporting moderate to severe burden. Conclusion: RA patients showed a tendency to understate their disease burden and as compared to that observed by caregivers who suffer from considerable level of burden.

Background: Long term use of NSAIDS is mainly accompanied by major health implications such as gastrointestinal erosions, ulcerations and nephrotoxicity. These side effects arise from local irritation by the carboxylic acid moiety, that is common to most of NSAIDs (topical effect), in addition to decreased cytoprotective prostaglandin production. Therefore, in the medicinal chemistry research area, there is an ongoing need for the discovery of new, potent and safer anti-inflammatory lead compounds devoid of the irritant carboxylic acid moiety. Methods: A series of new 3-substituted-2-thioxo-thieno[2,3-d]pyrimidine derivatives were synthesized through reacting the starting 3-amino-2-thioxo-thieno[2,3-d]pyrimidines with different aromatic aldehydes. The structure of all newly synthesized compounds was confirmed with spectral and elemental analyses. The synthesized thieno[2,3-d]pyrimidines were investigated for in vivo anti-inflammatory activity, using the carrageenan induced paw edema test. The possible antiinflammatory mechanism was also evaluated by determining the concentration of prostaglandin E2 (PGE2) in blood serum using a rat specific PGE2 ELISA kit. Results: All test compounds could significantly reduce carrageenan induced paw edema comparable to diclofenac sodium as a potent anti-inflammatory drug. Moreover, they could decrease the concentration of PGE2 in blood serum. Interestingly, compound 4c exhibited the most potent in vivo anti-inflammatory activity with protection of 35%, 36% and 42% against carrageenan-induced paw edema after 1h, 2h and 3h, representing 92%, 86% and 88% respectively of diclofenac activity. It also decreased the concentration of PGE2 in blood serum to 19 pg/ mL which is comparable to diclofenac with PGE2 concentration of 12 pg/ mL. Moreover, Compounds 4f, 4a, 4i and 4e exerted significant anti-inflammatory activity after 4h, representing 71%, 69%, 63% and 61% respectively of diclofenac activity. Furthermore, they significantly decreased the concentration of PGE2 in blood serum. Conclusion: These thienopyrimidines may be used as good candidates for the search of promising, potent and safe antiinflammatory leads for being free from acidic functions.