| Autor: |
Itoh, Kennosuke, Nakahara, Hiroki, Takashino, Atsushi, Hara, Aya, Katsuno, Akiho, Abe, Yuriko, Mizuguchi, Takaaki, Karaki, Fumika, Hirayama, Shigeto, Nagai, Kenichiro, Seki, Reiko, Sato, Noriko, Okuyama, Kazuki, Hashimoto, Masashi, Tokunaga, Ken, Ishida, Hitoshi, Mikami, Fusako, Kwofie, Kofi Dadzie, Kawada, Hayato, Lin, Bangzhong, Nunomura, Kazuto, Kanai, Toshio, Hatta, Takeshi, Tsuji, Naotoshi, Haruta, Junichi, Fujii, Hideaki |
| Zdroj: |
MedChemComm; 2024, Vol. 15 Issue: 12 p4001-4010, 10p |
| Abstrakt: |
The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the anti-schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability. Therefore, the discovery of a new class of anti-schistosomal agents is imperative. To address this challenge, we introduce a pioneering method for the synthesis of 1,2,5-oxadiazinane derivatives through the cycloaddition of nitrones with N,N,N′,N′-tetraalkyldiaminomethane in the presence of an IrIIIcomplex photosensitizer. This transformative reaction offers a streamlined route to various kinds of 1,2,5-oxadiazinanes that is characterized by mild reaction conditions and broad substrate scope. Mechanistic investigations suggest that the photoredox pathway underlies the [3 + 3] photocycloaddition process. Thus, based on bioisosteric replacement, we identified a remarkable molecule as a new chemotype of a potent anti-schistosomal compound that not only exhibits superior solubility, but also retains the potent biological activity inherent to PZQ. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
