Improving the Activity of Aminophenoxazinones: Synthesis, CPC Purification, and Phytotoxicity Potential

Aminophenoxazinones (APOs) are potent phytotoxic metabolites and histone deacetylase inhibitors, offering a low-resistance bioherbicide profile. This research synthesized a library of APO derivatives with targeted modifications to optimize physicochemical properties and biological activity using oxidative cyclocondensation. Purification challenges from strong compound-solid phase interactions were overcome by using centrifugal partition chromatography (CPC). Phytotoxicity was screened against <i>Lolium rigidum</i>, <i>Portulaca oleracea</i>, and <i>Plantago lanceolata</i>. While germination remained largely unaffected, compounds <b>10</b> and <b>11</b> caused significant root inhibition (77% and 89%, respectively for <i>P. oleracea</i>) at 1000 μM. Specifically, <b>11</b> reached inhibition levels comparable to the positive control, pendimethalin (86% for <i>P. oleracea</i>). Following a detailed structure-activity relationship analysis, <b>10</b> emerged as the most potent candidate, exhibiting an IC₅₀ of 4.5 μM against <i>P. oleracea</i> roots, considerably lower than that of natural <b>APO</b> (332.5 μM). These findings strongly validate this rational design and purification strategy, positioning <b>10</b> as a valuable agrochemical lead for sustainable weed management.