title: Structure-activity relationship (SAR) and preliminary mode of action studies of 3-substituted benzylthioquinolinium iodide as anti-opportunistic infection agents.
abstract: Opportunistic infections are devastating to immunocompromised patients. And in especially sub-Saharan Africa where the AIDS epidemic is still raging, the mortality rate was recently as high as 70%. The paucity of anti-opportunistic drugs, the decreasing efficacy and the development of resistance against the azoles and even amphotericin B have stimulated the search for new drugs with new mechanisms of action. In a previous work, we showed that a new chemotype derived from the natural product cryptolepine displayed selective toxicity against opportunistic pathogens with minimal cytotoxicity to normal cells. In this manuscript, we report the design and synthesis of substituted benzylthioquinolinium iodides, evaluated their anti-infective properties and formulated some initial structure-activity relationships around phenyl ring A from the original natural product. The sensitivity of the most potent analog 10l, to selected strains of C. cerevisiae was also evaluated leading to the observation that this scaffold may have a different mode of action from its predecessor, cryptolepine.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: Sidney
authors.initials: S
authors.lastname: Bolden
authors.forename: Xue Y
authors.initials: XY
authors.lastname: Zhu
authors.forename: Jagan R
authors.initials: JR
authors.lastname: Etukala
authors.forename: Comfort
authors.initials: C
authors.lastname: Boateng
authors.forename: Tryphon
authors.initials: T
authors.lastname: Mazu
authors.forename: Hernan
authors.initials: H
authors.lastname: Flores-Rozas
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Jacob
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: Seth Y
authors.initials: SY
authors.lastname: Ablordeppey
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005658:Fungi / Q000187:drug effects / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011806:Quinolinium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001688:Biological Products; D011806:Quinolinium Compounds
keywords: Anti-opportunistic infections; Antifungal agents; Benzylthioquinolinium iodides; Craig plot; Cryptolepine; Structure–activity relationships; Substituted quinolinium salts