Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors

Abstract

The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have reported the Mannich base-type derivatives of pyrrolo[3,4-d]pyridazinone which strongly inhibit cyclooxygenase, have better affinity to COX-2 isoenzyme and exert promising anti-oxidant activity. These findings encouraged us to perform further optimization of that structure. Herein, we present the design, synthesis, molecular docking, spectroscopic, and biological studies of novel pyrrolo[3,4-d]pyridazinone derivatives bearing 4-aryl-1-(1-oxoethyl)piperazine pharmacophore 5a,b–6a,b. The new compounds were obtained via convenient, efficient, one-pot synthesis. According to in vitro evaluations, novel molecules exert no cytotoxicity and act as selective COX-2 inhibitors. These findings stay in good correlation with molecular modeling results, which additionally showed that investigated compounds take a position in the active site of COX-2 very similar to Meloxicam. Moreover, all derivatives reduce the increased level of reactive oxygen and nitrogen species and prevent DNA strand breaks caused by oxidative stress. Finally, performed spectroscopic and molecular docking studies demonstrated that new compound interactions with bovine serum albumin (BSA) are moderate, formation of complexes is in one-to-one ratio, and binding site II (subdomain IIIA) is favorable.

A New N-Substituted 1H-Isoindole-1,3(2H)-Dione Derivative—Synthesis, Structure and Affinity for Cyclooxygenase Based on In Vitro Studies and Molecular Docking

“…It was found that the structural elements: the heterocyclic moiety, the hydroxyalkyl linker and the 4-substituted piperazine determine the high activity and affinity for 5-HT 1AR receptors [ 12 ]. The significant reactivity of the acid proton at the imide nitrogen atom allows for the preparation of many phthalimide derivatives, and the type of pharmacophore introduced into the molecule determines the direction of action of the new derivatives [ 13 , 14 , 15 , 16 , 17 ].…”

In Vitro and In Silico Evaluation of New 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone as Promising Cyclooxygenase Inhibitors

“…In the first step, we conducted the formation of Mannich base type derivatives 2a, b-4a, b through one-step reaction of 1a, b with appropriate disubstituted 4phenylpiperazine and 37% solution of formaldehyde in anhydrous ethanol, as it has already been described [32]. Subsequently, in order to achieve structures 5a, b-7a, b, the reaction of 1a, b was carried out in ethanol, alongside with the presence of sodium ethoxide and suitable 1-(2-chloro-1-oxoethyl)-4-disubstituted phenylpiperazine, as described in our earlier paper [31]. The formed precipitates were filtered off, washed with ethanol and purified by crystallization from this solvent.…”

“…In our previous paper, we have reported the synthesis of 1,3,4-oxadiazole based derivatives of pyrrolo [3,4-d]pyridazinone [31,32]. Introduction of 1,3,4-oxadiazole moiety to the pyrrolo [3,4-d]pyridazinone core was aimed to improve COX-2 affinity and reduce gastrotoxicity of investigated structures.…”

“…When considering previously reported molecules, different unsubstituted or monosubstituted arylpiperazine/arylpiperidine residues could be distinguished in their structure. Investigated derivatives revealed promising cyclooxygenase inhibitory activity-some of them acted as specific COX-2 inhibitors, the other ones were selective towards this enzyme [31,32]. Taking into account that the binding pocket of isoenzyme COX-2 is bigger than that of COX-1 [35], we decided to introduce spacious, double substituted arylpiperazine pharmacophore in order to improve the COX-2/COX-1 inhibitory ratio of titled compounds.…”

Editorial for Special Issue “Bioactive Oxadiazoles”

“…The 1,3,4-oxadiazole motif was inserted into two new classes of hybrid compounds, with anti-inflammatory activity, that exert selective COX-2 inhibition [ 1 , 2 ]. This oxadiazole isomer was also included in the structure of indole hybrid able to target Bcl-2, with in vitro pro-apoptotic activity [ 3 ].…”