Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds: Synthesis and evaluation against opportunistic fungal pathogens.
Substitution around 5-methyl benzothieno[3,2-b]quinolinium (2) ring system was explored in order to identify positions of substitution that could improve its antifungal profile. The 3-methoxy (10b) was active against C. albicans, C. neoformans, and A. fumigatus and the 4-chloro (10f) analog showed moderate increases in anti-cryptococcal and anti-aspergillus activities. The effectiveness of 10b and 10f were validated in murine models of candidiasis and cryptococcosis, respectively. The efficacy of 10f in reducing brain cryptococcal infection and its observation in the brain of mice injected with this quaternary compound confirm the capacity of these compounds to cross the blood-brain barrier of mice. Overall, several of the chloro and methoxy substituted compounds showed significant improvements in activity against A. fumigatus, the fungal pathogen prevalent in patients receiving organ transplant. Opening the benzothiophene ring of 2 to form 1-(5-cyclohexylpentyl)-3-(phenylthio)quinolinium compound (3) resulted in the identification of several novel compounds with over 50-fold increases in potency (cf. 2) while retaining low cytotoxicities. Thus, compound 3 constitutes a new scaffold for development of drugs against opportunistic infections.
College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA.
Comfort A
CA
Boateng
Suresh V K
SV
Eyunni
Xue Y
XY
Zhu
Jagan R
JR
Etukala
Barbara A
BA
Bricker
M K
MK
Ashfaq
Melissa R
MR
Jacob
Shabana I
SI
Khan
Larry A
LA
Walker
Seth Y
SY
Ablordeppey
D000818:Animals; D001812:Blood-Brain Barrier; D002177:Candidiasis / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005658:Fungi / Q000187:drug effects*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D020714:Maximum Tolerated Dose; D051379:Mice; D008826:Microbial Sensitivity Tests; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D011804:Quinolines