title: Synthesis, structure-activity relationship studies, and antibacterial evaluation of 4-chromanones and chalcones, as well as olympicin A and derivatives.
abstract: On the basis of recently reported abyssinone II and olympicin A, a series of chemically modified flavonoid phytochemicals were synthesized and evaluated against Mycobacterium tuberculosis and a panel of Gram-positive and -negative bacterial pathogens. Some of the synthesized compounds exhibited good antibacterial activities against Gram-positive pathogens including methicillin resistant Staphylococcus aureus with minimum inhibitory concentration as low as 0.39 μg/mL. SAR analysis revealed that the 2-hydrophobic substituent and the 4-hydrogen bond donor/acceptor of the 4-chromanone scaffold together with the hydroxy groups at 5- and 7-positions enhanced antibacterial activities; the 2',4'-dihydroxylated A ring and the lipophilic substituted B ring of chalcone derivatives were pharmacophoric elements for antibacterial activities. Mode of action studies performed on selected compounds revealed that they dissipated the bacterial membrane potential, resulting in the inhibition of macromolecular biosynthesis; further studies showed that selected compounds inhibited DNA topoisomerase IV, suggesting complex mechanisms of actions for compounds in this series.
authors.affiliation: Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo , 34 Rainbow Drive, Hilo, Hawaii 96720, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Maddox
authors.forename: Md Zahidul
authors.initials: MZ
authors.lastname: Alam
authors.forename: Lissa S
authors.initials: LS
authors.lastname: Tsutsumi
authors.forename: Gagandeep
authors.initials: G
authors.lastname: Narula
authors.forename: David F
authors.initials: DF
authors.lastname: Bruhn
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Wu
authors.forename: Shayna
authors.initials: S
authors.lastname: Sandhaus
authors.forename: Robin B
authors.initials: RB
authors.lastname: Lee
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Simmons
authors.forename: Yuk-Ching
authors.initials: YC
authors.lastname: Tse-Dinh
authors.forename: Julian G
authors.initials: JG
authors.lastname: Hurdle
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
authors.forename: Dianqing
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047188:Chalcones / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D002522:Chlorocebus aethiops; D002867:Chromones / Q000737:chemistry*; D027081:DNA Gyrase; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D047188:Chalcones; D002867:Chromones; D059005:Topoisomerase II Inhibitors; C571760:olympicin A; C068514:4-chromanone; D010696:Phloroglucinol; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase