Abstract
A new series of 1-(4-Acetylphenyl)-7,7-dimethyl-3-(substitutedphenyl)-1,2,3,4,7,8-octahydroquinazolin-5(6H)-ones (6-15) were synthesized and tested against COX-1 and COX-2 enzymes. Those compounds exhibited strong interaction at the COX-2 binding site and poor interaction at the COX-1 active site. Subjected to in vitro cyclooxygenase COX-1/COX-2 inhibition assay; most of the compounds especially compounds 6, 7, 12, 13, and 16 exhibited potent anti-inflammatory effects, selective COX-2 inhibition, with half-maximal inhibitor concentration (IC50) values of 0.22–1.42 μM and selectivity index (SI) values of 6.16–14.18 compared with celecoxib (IC50 = 0.05 μM and COX-2 SI: 296), diclofenac (IC50 = 0.8 μM and COX-2 SI: 4.87), and indomethacin (IC50 = 0.49 μM and COX-2 SI: 0.08) as reference drugs. Docking study has been carried out to confirm the binding affinity and selectivity of the most active compound (compound 6) to COX-2 enzyme.
Highlights
Pain and inflammation are very commonly associated with numerous pathological conditions commonly prescribed with nonsteroidal anti-inflammatory drugs (NSAIDs)
The new compounds were confirmed using High Resolution Mass Spectrometry and elemental analyses and various spectroscopic methods. 1H-NMR spectrum proved the disappearance of both singlets at δ= 7.85 ppm (NH group) and at δ= 5.65 of starting enaminone 5 and appearance of two characteristic singlets at δ= 4.88 and 4.21 ppm indicating the formation of two methylene groups at 2- and 4-position of the quinazoline skeleton.13C-NMR spectra proved the proposed 5-oxo-octahydroquinazolin structures due to the appearance of characteristic peaks around δ = 69.68 and 50.35 ppm which were assignable to C2- and C4- of the quinazoline nucleus
The results showed that the reference drugs; celecoxib (CEL), diclofenac (DCF) and indomethacin (INM) exhibited cyclooxygenase enzyme (COX)-1 inhibitory activity with IC50 14.8, 3.9 and 0.039 μM respectively and COX-2 inhibitory activity with IC50 0.05, 0.8 and 0.49 μM respectively
Summary
Pain and inflammation are very commonly associated with numerous pathological conditions commonly prescribed with nonsteroidal anti-inflammatory drugs (NSAIDs). There is continuous development of new drugs that have potent anti-inflammatory activity, with minimum side effects and high safety margin (1, 2). The design of effective agents that have fast action and provide relief from pain and inflammation is a major challenge for medicinal chemists such as our novel quinazolinone as non-acidic NSAIDs. Cyclic -diketones are an important class of organic compounds, one of which is 5,5-dimethyl 1,3-cyclohexandione (Dimedone) which is used as a precursor for the preparation of different intermediates such as enaminones and different heterocyclic rings such as quinazoline, quinoline, acridine and hydrazone derivatives that have interesting biological activities. The choice of quinazolinone heterocycle as a central core was fundamental due to its presence in the potent anti-inflammatory natural alkaloids rutaecarpine[1] and tryptanthrin[2] (3)
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