title: Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).
abstract: Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKaand lower log D7.4values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Sriraghavan
authors.initials: S
authors.lastname: Kamaraj
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Vivek J
authors.initials: VJ
authors.lastname: Bulbule
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Francis C K
authors.initials: FC
authors.lastname: Chiu
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, CH-4002 Basel, Switzerland.|University of Basel , CH-4003 Basel, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Chollet
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Manickam
authors.initials: M
authors.lastname: Dhanasekaran
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Hein
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, CH-4002 Basel, Switzerland.|University of Basel , CH-4003 Basel, Switzerland.
authors.forename: Petros
authors.initials: P
authors.lastname: Papastogiannidis
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Helena
authors.initials: H
authors.lastname: Barker
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, CH-4002 Basel, Switzerland.|University of Basel , CH-4003 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Scheurer
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Tang
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.affiliation: Basilea Pharmaceutica Ltd. , Grenzacherstrasse 487, CH-4058 Basel, Switzerland.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Urwyler
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.affiliation: F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Hugues
authors.initials: H
authors.lastname: Matile
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, CH-4002 Basel, Switzerland.|University of Basel , CH-4003 Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Jonathan L
authors.identifier: 0000-0003-0075-2336
authors.initials: JL
authors.lastname: Vennerstrom
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D051379:Mice; D010545:Peroxides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D010545:Peroxides; D000218:Adamantane; C558165:artefenomel