| Summary: | Human African trypanosomiasis is an endemic infectious disease caused by <i>Trypanosoma brucei</i> via the bite of tsetse-fly. Most of the drugs used for the treatment, e.g., Suramin, have shown several problems, including the high level of toxicity. Accordingly, the discovery of anti-trypanosomal drugs from natural sources has become an urgent requirement. In our previous study on the anti-trypanosomal potential of <i>Euphorbia</i> species, <i>Euphorbia abyssinica</i> displayed significant anti-trypanosomal activity. Therefore, a phytochemical investigation of the methanolic extract of <i>E. abyssinica</i> was carried out. Twelve compounds, including two triterpenes (<b>1</b>, <b>2</b>); one sterol-glucoside (<b>4</b>); three ellagic acid derivatives (<b>3</b>, <b>9</b>, <b>11</b>); three gallic acid derivatives (<b>5</b>, <b>6</b>, <b>10</b>); and three flavonoids (<b>7</b>, <b>8</b>, <b>12</b>), were isolated. The structures of isolated compounds were determined through different spectroscopic techniques. Compound (<b>10</b>) was obtained for the first time from genus <i>Euphorbia</i> while all other compounds except compound (<b>4</b>), were firstly reported in <i>E. abyssinica</i>. Consequently, an in silico study was used to estimate the anti-trypanosomal activity of the isolated compounds. Several compounds displayed interesting activity where 1,6-di-<i>O</i>-galloyl-<span style="font-variant: small-caps;">d</span>-glucose (<b>10</b>) appeared as the most potent inhibitor of trypanosomal phosphofructokinase (PFK). Moreover, molecular dynamics (MD) simulations and ADMET calculations were performed for 1,6-di-<i>O</i>-galloyl-<span style="font-variant: small-caps;">d</span>-glucose. In conclusion, 1,6-di-<i>O</i>-galloyl-<span style="font-variant: small-caps;">d</span>-glucose revealed high binding free energy as well as desirable molecular dynamics and pharmacokinetic properties; therefore, it could be suggested for further in vitro and in vivo studies for trypanosomiasis.
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