Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds: Synthesis and evaluation against opportunistic fungal pathogens

Abstract

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.

CoMFA studies and in vitro evaluation of some 3-substituted benzylthio quinolinium salts as anticryptococcal agents

“…The training set includes compounds from three scaffolds: the phenylthioether ( 3 ), benzylthioether ( 4 ), sulfoxide ( 5 ) ring-opened analogs of cryptolepine and consists of the most potent pharmacophore groups found during the optimization of the lead compound (Fig 2). The pIC 50 activity data, originally reported in μg/mL 11–12 and converted to μM for compounds that inhibited C. neoformans, had a range of at least 3 log units that provided a starting point in the development of an alignment hypothesis.…”

“…11–12 To obtain the rest of the compounds in the training and test set ( 4a-f ), 3-iodoquinoline ( 6 ) was required as the starting material and was obtained by refluxing 3-bromoquinoline in the presence of CuI, NaI and N, N′-dimethylethylamine in 1,4-dioxane under N 2 . A mixture of 3-iodoquinoline, substituted phenyl-methanethiol, CuI and ethylene glycol, in 2-propanol was stirred under microwave irradiation to give substituted 3-(benzylthio)quinolines.…”

“…5,6 During optimization of cryptolepine to improve its anti-infective properties, several resulting analogs have demonstrated increased potency and lower cytotoxicity than CLP. 7–11 These analogs span six different scaffolds and have generated important structure activity relationship (SAR) data. The encouraging progress made during the optimization process spurred a need to develop a CoMFA model that would enable the prediction of subsequently designed analogs prior to their synthesis and thus, aid in the prioritization of the synthesis of designed analogs.…”

“…11–12 The original lead compound (1), reportedly operates through a unique antifungal mechanism of action which differs from current drugs on the market by intercalating into DNA and inhibiting topoisomerase II. 13 The analogs in this paper are thought to operate through a similar mechanism of action but with a lower degree of intercalation into DNA due to the loss of the flat topography when the B-ring of the tetracyclic structure is opened.…”

<strong>Synthesis of Chiral Heteroaryl-Substituted Dihydropyran Derivatives via Ring Closing Enyne Metathesis Reaction</strong>

“…Their natural and synthetic derivatives display a wide spectrum of pharmacological activities like antioxidant, antibacterial, antimicrobial, antifungal, antiviral and anticancer activities etc [13][14][15][16][17]. Moreover substituted benzofurans find application such as of oxidant [18], antioxidants, fluorescent sensor [19], brightening agents, a variety of drugs and in other field of chemistry and agriculture [20].…”