Synthesis of morphinan compounds having drug-resistance reversal activity against drug-resistant malaria and the influence of thiol group-trapping ability

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K05710
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: University of Tsukuba
• Principal Investigator: Kutsumura Noriki 筑波大学, 国際統合睡眠医科学研究機構, 教授 (00439241)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: モルヒナン / オピオイド / グルタチオン / チオール捕捉能 / 抗マラリア / 抗トリコモナス / 耐性解除 / 構造活性相関

Outline of Final Research Achievements

We have reported that BNTX derivatives containing a morphinan moiety have drug-resistance reversing effect in Plasmodium chabaudi and antitrichomonal activities, and speculated that the thiol group-trapping ability in vivo of the unsaturated double bond in the compounds is involved in these mechanisms of action. To experimentally prove this hypothesis, a structure-activity relationship study was conducted between thiol-group trapping ability and in vitro chloroquine-resistant antimalarial activities. As a result, we have found that the morphinan with stronger antimalarial activity tends to have stronger thiol group-trapping activity. These results suggest that the thiol group-trapping ability in the morphinan-lead compounds might be used as a primary screening for evaluation of antimalarial activity. In addition, we also discovered novel rearrangement reactions in the morphinan skeleton and the resulting product’s intriguing biological activities.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

マラリア撲滅のため、新規作用機序を持つ薬物開発は多くの製薬企業や大学の創薬研究機関で行われており、本提案研究と同様に、原虫の生息する赤血球内のグルタチオン濃度の制御を鍵とした研究も少なくない。しかし、直接グルタチオンそのものを標的とした研究報告はごく一部であり、しかもドラッグライクな構造であるモルヒナン骨格を基盤とする抗原虫薬の開発研究は報告例が無く、本研究の推進には大きな意義がある。