Polyhydroquinoline Amides: Comprehensive Study on Synthesis, In Vivo Biological Activities, and Computational Analysis Including Molecular Docking, DFT, and ADMET

Twenty-four new amide derivatives of polyhydroquinoline <b>(1-25)</b> were synthesized, deduced structurally, and evaluated for in vivo anti-inflammatory, analgesic, and calcium channel-blocking activities. Before performing experiments in vivo<i>,</i> we performed FMO analysis based on TD-DFT/B3PW91-D3/6-311G++** calculations, displaying a combination of favorable reactivity indices for all compounds <b>(2-25)</b>, including low <i>E</i> _g values, high softness, and balanced electronegativity and electrophilicity. Their diverse structural features for all compounds suggest that they may interact with different biological targets or have varying mechanisms of action. The in vivo evaluation of the anti-inflammatory analgesic and calcium channel-blocking effects was carried out in mice and rats, respectively. A carrageenan-induced paw edema model was adopted to measure the reduction in paw volume. An acetic acid-induced writhing test was conducted to evaluate the writhing response in mice. Additionally, isolated aortic ring preparations from rats were used to investigate the potential calcium channel-blocking effect against high K⁺-induced contraction in the organ bath assembly. In the series, seven derivatives <b>2, 7, 12, 22, 25, 8,</b> and <b>18</b> exhibited potent activity, with 83.33-80.00% decreases in edema, which is closer to the value of the standard compound indomethacin, showing 86.95%. Similarly, the remaining derivatives exhibited significant to less activity, showing 76.92-47.36% decreases in edema. In the case of analgesic activity, all of the products significantly increased the pain threshold time, mainly, compounds <b>18, 23,</b> and <b>10,</b> which had the best analgesic effects of 18.92 ± 1.10, 18.91 ± 1.81, and 17.00 ± 1.28 s, respectively, when compared with indomethacin as the standard (20.00 ± 1.60) using the hot plate test. Likewise, in the acetic acid-induced writhing test, six compounds showed potent inhibitory effects from 76.82 to 63.29%, while in CCB activity against high K⁺ (80 mM) in aortic ring preparations, compound <b>7</b> showed the maximum vasorelaxant effect with an EC₅₀ value of 2.24 μg/mL (1.0-3.48). The most active compounds form a stable complex on the active site of the prostaglandin endoperoxide synthase II enzyme, which was confirmed by a docking study using amino acid binding pockets occupied by the reference drug indomethacin.