Identification of 3-phenylaminoquinolinium and 3-phenylaminopyridinium salts as new agents against opportunistic fungal pathogens

Abstract

Previous studies on the indoloquinoline alkaloid, cryptolepine (2), revealed that it has antii-nfective properties among other activities. Using Structure-activity relationship (SAR) techniques, several ring-opened analogs of cryptolepine (3-phenylaminopyridinium and 3-phenylaminoquinolinium derivatives) were designed to improve the potency and lower the cytotoxicity shown by several of the precursor agents. Results indicate that these ring-opened analogs constitute new anti-infective agents with over a 100-fold potency and several fold lower cytotoxicity than cryptolepine from which they are derived.

Scheme I

Reagents and conditions: (i) CH₂Cl₂, Cu(OAc)₂, TEA, MS-Powder, RT, 12–24 hr; (ii) Pd(OAc)₂, CF₃COOH, 80 °C, 6 h; (iii) CH₃I, Toluene 110 °C, 12–24 h, sealed tube.

Scheme II

(i) Aqueous KOH, 10 days. (ii) Paraffin oil, 300 °C, 3 h.; (iii) NaH, R₁-I, DME, rt, 12 h; (iv) CH₃I, Toluene, 110 °C, 12–24 h or CH₃OTf, Toluene, rt, 24 h.

Scheme III

Reagents and conditions :( i) 1, 5-Dibromopentane, Li₂CuCl₄, THF, 0°C, 12 h, (ii) NaI, Acetone, Reflux, 12h.

Scheme IV

Reagents and conditions: (i) NaH, Cyclohexylpentyl iodide, DME, RT, 12 h; (ii) CH₃I, Toluene 110 °C, 12–24 h

Scheme V

Reagents and conditions: (i) (Y = B(OH)₂), CH₂Cl₂, Cu(OAc)₂, TEA, Molecular sieve, RT, 24 h, (Y = Br, I) Dioxane, Pd(OAc)₂ , 80°C, 24 h; (ii) DME, 5-iodo-pentylcyclohexane, NaH, 0°C, RT, 12 h; (iii) CH₃I, Toluene, 110°C, 12 h.