Synthesis and Antiinflammatory Evaluation of 9-Anilinoacridine and 9-Phenoxyacridine Derivatives

Abstract

Mast cells, neutrophils, and macrophages are important inflammatory cells that have been implicated in the pathogenesis of acute and chronic inflammatory diseases. To explore a novel antiinflammatory agent, we have synthesized two types of acridines, 9-anilinoacridine and 9-phenoxyacridine derivatives, for evaluation on the grounds that acridine is a versatile heterocycle possessing a wide variety of biological properties. The title compounds were synthesized by reaction of 9-chloroacridine with appropriate Ar-NH(2) and Ar-OH, and their antiinflammatory activities on inhibitory effects on the activation of mast cells, neutrophils, and macrophages were studied. Three acridine derivatives 4, 10, and 11 were proved to be more potent than the reference inhibitor mepacrine for the inhibition of rat peritoneal mast cell degranulation with similar IC(50) values (16-21 microM). Compound 3 also showed potent inhibitory activity (IC(50) = 8.2 and 4.4 microM, respectively) for the secretion of lysosomal enzyme and beta-glucuronidase from neutrophils. Moreover, compounds 5 and 9 were shown to be efficacious inhibitors of TNF-alpha production in macrophage-like cell lines RAW 264.7. Compounds 2 and 12 were the potent inhibitors of TNF-alpha production in murine microglial cell lines N9. To further explore the cytotoxic properties of these acridine derivatives, (E)-12 was selected for NCI's in vitro disease-oriented tumor cells screen. The results indicated that this compound had no significant cytotoxicity with a mean GI(50) of 58.0 microM. These results indicated that the antiinflammatory effects of acridine derivatives were mediated, at least in part, through the suppression of chemical mediators released from mast cells, neutrophils, and macrophages and that these compounds have the potential to be novel antiinflammatory agents with no significant cytotoxicity.

Efficacy of Novel Acridine Derivatives in the Inhibition of hPrP90-231 Prion Protein Fragment Toxicity

“…Presently it is superseded in both uses by other drugs inducing milder side effects, but it is still proposed for the treatment of giardiasis and systemic lupus erythematosus (Brunton et al 2006). Moreover it is observed an ongoing reappraisal of quinacrine and novel acridine derivatives for the treatment of parasitic (e.g., Trypanosomiasis) and rheumatic diseases (Bonse et al 1999;Anderson et al 2006;Chen et al 2002;Wallace 1989). In more recent years, quinacrine was found to possess a potent antiprion activity in vitro, inhibiting PrP Sc formation in scrapie-infected neuroblastoma cells N2a (Doh-Ura et al 2000;Korth et al 2001), prompting the compassionate use of this drug in clinics for the treatment of CJD (Stewart et al 2008).…”

Synthesis of substituted acridinyl pyrazoline derivatives and their evaluation for anti-inflammatory activity

“…6.1.8. General procedure for the synthesis of 1-(2 0 ,4 0 -di substituted acridin-9 0 -yl)-3-methyl pyrazol-5-one (7)(8)(9)(10)(11)(12) A mixture of compounds 1-6 (0.01 mol) and ethyl acetoacetate (0.01 mol) was refluxed in methanol (25 mL), containing concentrated hydrochloric acid (1 mL) for 10-15 h on a water bath. The resulting solution was then concentrated and cooled at room temperature.…”

“…The pyrazolines have been gaining prominence due to the fact that its derivatives have been found to possess wide spectrum of activities like anti-inflammatory [3][4][5][6][7], analgesic [7] and anticonvulsant [8,9]. In addition various heterocyclic compounds containing acridinyl moieties [10] were also possess quite interesting anti-inflammatory activity. In the light of these facts the pyrazolines by incorporation of acridinyl at the first position and oxadiazolyl [11] moieties at third position have been synthesized.…”

Quinoline Oximes: Synthesis, Reactions, and Biological Activity. (Review)

“…The oximes of furo[2,3-b]quinoline 129 and 130 [65,141] and 9-phenoxy-or 9-anilinoacridine [142] were proposed as anti-inflammatory agents. In addition, the quinoline-4-carbaldehyde oxime exhibited bronchodilatory activity [149].…”