title: Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors.
abstract: A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-positive pathogens particularly staphylococcal organisms. Most of the compounds from the series possessed excellent biochemical inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clinically relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, AEA16, in Escherichia coli FabI enzyme was determined unambiguously using X-ray crystallography. The lead compounds displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Takhi
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Kandepu
authors.initials: K
authors.lastname: Sreenivas
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Chandrashekar K
authors.initials: CK
authors.lastname: Reddy
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Mahadari
authors.initials: M
authors.lastname: Munikumar
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Kolakota
authors.initials: K
authors.lastname: Praveena
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Pabolu
authors.initials: P
authors.lastname: Sudheer
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Bandaru N V M
authors.initials: BN
authors.lastname: Rao
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Gollamudi
authors.initials: G
authors.lastname: Ramakanth
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Jampala
authors.initials: J
authors.lastname: Sivaranjani
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Shardaprasad
authors.initials: S
authors.lastname: Mulik
authors.affiliation: Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Yeruva R
authors.initials: YR
authors.lastname: Reddy
authors.affiliation: Aurigene Discovery Technologies Ltd, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560 100, India.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Narasimha Rao
authors.affiliation: Aurigene Discovery Technologies Ltd, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560 100, India.
authors.forename: Rentala
authors.initials: R
authors.lastname: Pallavi
authors.affiliation: Aurigene Discovery Technologies Ltd, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560 100, India.
authors.forename: Anirudha
authors.initials: A
authors.lastname: Lakshminarasimhan
authors.affiliation: Aurigene Discovery Technologies Ltd, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560 100, India.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Panigrahi
authors.affiliation: Aurigene Discovery Technologies Ltd, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560 100, India.
authors.forename: Thomas
authors.initials: T
authors.lastname: Antony
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Iskandar
authors.initials: I
authors.lastname: Abdullah
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Yean K
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Aurigene Discovery Technologies Ltd, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560 100, India.
authors.forename: Murali
authors.initials: M
authors.lastname: Ramachandra
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Rohana
authors.initials: R
authors.lastname: Yusof
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Noorsaadah A
authors.initials: NA
authors.lastname: Rahman
authors.affiliation: Aurigene Discovery Technologies Ltd, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560 100, India. Electronic address: hosahalli_s@aurigene.com.
authors.forename: Hosahalli
authors.initials: H
authors.lastname: Subramanya
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001384:Azetidines / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000166:cytology / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001384:Azetidines; D004791:Enzyme Inhibitors; C082735:azetidine; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: Antibacterial; Azetidine; Ene-amide; Enoyl ACP reductase; FabI inhibitor