To Synthesize and Explore Anti-Inflammatory Potentials of Ketone and Ketoester Derivatives of Succinimides

In the current scenario, one of the most key health issues in the world is inflammation. Inflammation is a body defense mechanism. It is the local response of living tissues to injury in order to eliminate or limit the spread of injurious agent. Heat, redness, swelling, pain, and loss of function are the main symptoms to identify it. That involves three phases like vasodilatation, phagocytic migration and tissue repair. Many medications like non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are available to prevent or minimize the progression of the inflammatory diseases. NSAIDs are associated with several side effects. Their prolonged use may causes bone marrow depression, gastric intolerance, kidney failure, water and salt retention, liver failure, ulcers and prolonged bleeding after an injury or surgery. Thus, most antiinflammatory drugs have a number of adverse effects hence there is a need to develop a safe and new anti-inflammatory drug with minimum side effects. On the other hand, cyclic imides possess structural features which conferred potential biological activity and pharmaceutical use. The various classes of cyclic imides have received greater attention due to the COX-2 inhibition, anti-inflammatory activity. Based on this, we synthesized various ketone and ketoester derivatives of succinimides. Among the synthesized compound total of ten (10) compounds were newly synthesized. All the compounds obtained were purified with pen/pencil column. The pure compounds obtained were identified with various techniques i.e., mass spectroscopy, carbon NMR and proton NMR. After confirmation of their structure, they were subjected to in-vitro anti-inflammatory assay using cyclooxygenase (COX-2) and 5- lipoxygenase (5-LOX) enzyme. In COX-2 in-vitro enzyme inhibitory assay, compound SJ-17, SJ-15 and SJ-2 were the most potent compound that displayed IC50 value of 0.98, 2.10 and 19.98 μM respectively. While in ketoesters derivatives of succinimides the tested compound SJ-18 and SJ-22 were displayed the most potent activity against COX-2 enzyme with IC50 value of 61.07 and 43.21 μM. In 5-LOX in-vitro enzyme inhibition assay SJ-17 and SJ-13 were more potent with IC50 values of 0.86 and 0.81 µM respectively. The tested compound SJ-2 and SJ-11 also showed the best activity with IC50 value of 36 and 21.31 µM. While in ketoester derivatives the SJ-22 displayed excellent 5- LOX inhibition with IC50 of 33.57 µM respectively. All the synthesized compounds were then subjected to preliminary in-vivo anti-inflammatory study to confirm the anti-inflammatory effect. In carrageenan induced paw edema three doses of each tested compounds were applied. Among the tested compounds SJ-17 was the most potent and significantly inhibited the inflammation produced by carrageenan up to 55.17 ± 1.36 % after 1 h at 100 mg/kg. The maximal percent inhibition of paw edema was observed to be 68.22 ± 2.44 at 5th h. Second highest activity was displayed by SJ-11 with 61.97 ± 3.24 % inhibition. Likewise, tested compounds SJ-2 and SJ-22 also exhibited excellent activity with 55.07 ± 2.33 and 54.77 ± 1.55 % inhibitions at 100 mg/kg body weight (b.wt). Aspirin was used as a positive control in this assay which displayed 57.64 ± 1.55 % inhibition. The other entire synthesized compounds displayed moderate to good activity in carrageenan induced inflammation. In arachidonic acid induced ear inflammation, again SJ-17 was the most potent compound with 76.70 ± 2.24 % inhibition of ear edema at 100 mg/kg b.wt. While tested compound SJ-11 exhibited 63.88 ± 2.66 % inhibition. The tested compound SJ-2 and SJ-22 displayed 56.30 ± 1.24 and 63.81 ± 1.24 % activity. All the other compounds in this assay illustrated moderate to good activity. Furthermore, based on the in-vitro and in-vivo preliminary anti-inflammatory results the potent compounds were subjected to various inflammatory mediators like histamine, bradykinin, prostaglandin (PGE2) and leukotriene for the mechanism confirmation of the synthesized compounds. The compounds SJ-2, SJ-11, SJ-17 and SJ-22 were found to be the most effective among all the synthesized compounds. In histamine induced inflammation, tested compound SJ-17 has shown good activity (34.86 %, at 2nd h). The other tested compounds SJ-2, SJ-11and SJ-22 were less effective with 17.19, 25.38 and 11.11 % inhibition in this assay. The positive control cetirizine displayed 71.64 % inhibition. In bradykinin induced paw edema test SJ-2, SJ-11, SJ-17 and SJ-22 exhibited less activity while causing 7.37 ± 1.10, 4.42 ± 1.89, 15.28 ± 2.19 and 9.72 ± 3.13 % inhibition at 1st h. While the antagonist icatibant (HOE 140) showed dose dependent and significant inhibition 65.54 ± 3.61 % after 1 hour and remained significant until 5th h. Whereas, in prostaglandin E2 (PGE2) inflammatory mediator tested compound SJ-17 was the most potent and dose dependent causing 81.08 ± 2.03 % inhibition at 4th h. Similarly, SJ-11 exhibited 72.03 ± 3.24 % activity at 4th h which was the second active compound in this study. Likewise, the SJ-2 and SJ-22 also give excellent results with 64.33 ± 1.59 and 51.87 ± 3.24 % inhibitions at 4th h after the injection of phlogistic agent PGE2. Moreover, in leukotriene induced inflammation assay, the tested compound SJ-17 was again potent and give a promising result with 74.11 ± 3.58 % inhibition. SJ-11 was the second high active compound causing 58.13 ± 2.25 % inhibition. The tested compound SJ-2 was exhibited 49.08 ± 2.93 % activity while SJ-22 is less effective as compared to other tested compounds and exhibited 38.41 ± 3.07 % activity. From the current investigation it is clear that the compounds SJ-17, SJ-11 and SJ-2 have been verified to combat inflammation especially dual inhibition of COX-2 and 5-LOX. And inhibited both lipoxygenas as well as cyclooxygenase pathways of arachidonic acid metabolites supported by the mild anti-histaminic effect. So further work should be performed by the dosage form designing for these compounds to hit the market.