Design, synthesis, pharmacological evaluation, and <i>in silico</i> studies of the activity of novel spiro pyrrolo[3,4-<i>d</i>]pyrimidine derivatives

Abstract

In the present study, spiro compounds are shown to have distinctive characteristics because of their interesting conformations and their structural impacts on biological systems. A new family of functionalized spiro pyrrolo[3,4-<i>d</i>]pyrimidines is prepared <i>via</i> the one-pot condensation reaction of amino cyclohexane derivatives with benzaldehyde to prepare fused azaspiroundecanedione and azaspirodecenone/thione derivatives. A series of synthesized spiro compounds were scanned against DPPH and evaluated for their ability to inhibit COX-1 and COX-2. All compounds exhibit significant antiinflammatory activity, and they inhibited both COX-1 and COX-2 enzymes with a selectivity index higher than celecoxib as a reference drug. The most powerful and selective COX-2 inhibitor compounds were 11 and 6, with selectivity indices of 175 and 129.21 in comparison to 31.52 of the standard celecoxib. However, candidate 14 showed a very promising antiinflammatory activity with an IC₅₀ of 6.00, while celecoxib had an IC₅₀ of 14.50. Our findings are promising in the area of medicinal chemistry for further optimization of the newly designed and synthesized compounds regarding the discussed structure-activity relationship study (SAR), in order to obtain a superior antioxidant lead compound in the near future. All chemical structures of the novel synthesized candidates were unequivocally elucidated and confirmed utilizing spectroscopic and elemental investigations.