In Vitro Enzymatic and Computational Assessments of Pyrazole–Isatin and Pyrazole–Indole Conjugates as Anti-Diabetic, Anti-Arthritic, and Anti-Inflammatory Agents

<b>Background/Objectives</b>: Recently, the prevalence of diseases such as diabetes, arthritis, and inflammatory diseases, along with their complications, has become a significant health problem. This is in addition to the various biomedical applications of pyrazole, isatin, and indole derivatives. Accordingly, cooperation will continue between chemistry scientists, pharmaceutical scientists, and human doctors to produce hybrid compounds from pyrazole with isatin or indole possessing biological activities as anti-diabetic, anti-arthritic, and anti-inflammatory agents. <b>Methods</b>: The two series of pyrazole-isatin conjugates <b>12a</b>-<b>h</b> and pyrazole-indole conjugates <b>14a</b>-<b>d</b> were prepared from our previous works via the direct reaction of 5-amino-pyrazoles <b>10a</b>-<b>d</b> with <i>N</i>-alkyl isatin <b>11a</b>,<b>b</b>, and 1<i>H</i>-indole-3-carbaldehyde (<b>13</b>), respectively, using the previously reported procedure. The potential biological activities of <b>12a</b>-<b>h</b> and <b>14a</b>-<b>d</b> as anti-diabetic, anti-arthritic, and anti-inflammatory agents were assessed through estimated inhibition percentage (%) and the median inhibitory concentrations (IC₅₀) using methods described in the literature. Further, the computational assessments of <b>12a</b>-<b>h</b> and <b>14a</b>-<b>d</b> such as toxic doses (the median lethal dose, LD₅₀), toxicity classes, drug-likeness model scores (DLMS), molecular lipophilicity potential (MLP) maps, polar surface area (PSA) maps, and topological polar surface area (TPSA) values were predicted using available free websites. <b>Results</b>: The in vitro enzymatic assessment results showed that pyrazole-indole conjugate <b>14b</b> possesses powerful activities against (i) α-amylase (% = 65.74 ± 0.23, IC₅₀ = 4.21 ± 0.03 µg/mL) and α-glucosidase (% = 55.49 ± 0.23, IC₅₀ = 2.76 ± 0.01 µg/mL); (ii) the protein denaturation enzyme (% = 49.30 ± 0.17) and against the proteinase enzyme (% = 46.55 ± 0.17) with an IC₅₀ value of 6.77 ± 0.01 µg/mL; (iii) the COX-1, COX-2, and 5-LOX enzymes with an IC₅₀ of 5.44 ± 0.03, 5.37 ± 0.04, and 7.52 ± 0.04, respectively, which is almost close to the IC₅₀ of the indomethacin and zileuton drugs. Also, the computational assessment results showed (i) the conjugate <b>14b</b> possesses lipophilic surface properties thus can cross cell membranes, and is effective for treatment; (ii) all the conjugates possess a TPSA value of more than 140 Ų thus possess good intestinal absorption. <b>Conclusions</b>: The two series of pyrazole-isatin conjugates <b>12a</b>-<b>h</b> and pyrazole-indole conjugates <b>14a</b>-<b>d</b> were synthesized from our previous works. The results of these in vitro enzymatic and computational assessments concluded that the pyrazole-indole conjugate <b>14b</b> possesses powerful activities against various studied enzymes and possesses good computational results. In the future, our research team will present in vitro, in vivo biological, and computational assessments to hopefully obtain effectual agents such as anti-diabetic, anti-arthritic, and anti-inflammatory.