title: Development of a new air-stable structure-simplified nafuredin-γ analog as a potent and selective nematode complex I inhibitor.
abstract: Nafuredin-γ, obtained from natural nafuredin, has demonstrated a potent and selective inhibitory activity against nematode complex I. However, nafuredin-γ is unstable in air since its conjugated dienes are oxygen-labile. The instability in air was naturally solved by the synthesis of structure-simplified nafuredin-γ analogs without conjugated dienes. However, these modified analogs showed lower complex I inhibitory activities. Therefore, new air-stable structure-simplified nafuredin-γ analogs were designed and synthesized herein. Among all analogs synthesized, the one bearing a unique 1-azabicyclo[3.1.0]hexane scaffold showed the highest inhibitory activity (IC50=170 nM) while presenting high selectivity against nematode complex I.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohtawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Arima
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Shimizu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Hanatani
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Shimizu
authors.affiliation: Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Kazuro
authors.initials: K
authors.lastname: Shiomi
authors.affiliation: School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.|Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ōmura
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Nagamitsu
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009348:Nematoda / Q000187:drug effects*; D010100:Oxygen / Q000737:chemistry; D011753:Pyrones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000969:Antinematodal Agents; D004791:Enzyme Inhibitors; D011753:Pyrones; C423563:nafuredin; D042967:Electron Transport Complex I; D010100:Oxygen