Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Abstract

Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual stage activity against both liver stage and blood stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: 1) Picomolar inhibition of in vitro Plasmodium falciparum blood stage growth against multi-drug resistant parasites; 2) Curative efficacy after oral administration in erythrocytic P. yoelii murine malaria model; 3) Prevention of in vitro P. berghei sporozoite-induced development in human hepatocytes; and 4) Protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver stage antimalarial activity in acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

Boron trifluoride etherate promoted microwave-assisted synthesis of antimalarial acridones

“…25 Substrates 1d-1z, and 1aa were synthesized using Buchwald-Hartwig cross-coupling methods. 12,26 Representative procedure for the synthesis of acridin-9(10H)one (2a) 21 BF 3 .Et 2 O (580 mL, 4.69 mmol) was added to a microwave reaction vial containing N-phenylanthranilic acid (1a) (500 mg, 2.34 mmol). Then the reaction mixture was exposed to microwave irradiation for 1.0 min at 150 C. Aer cooling to room temperature, the reaction mixture was poured into water (25 mL) and allowed to stir for 5 min.…”

“…1) are of worldwide interest because of their wide range of biological properties, including antitumor, anticancer, antimalarial, anti-HIV, antiviral, and antifungal activities. [1][2][3][4][5][6][7][8][9][10][11][12][13] The intriguing structural features and therapeutic importance of acridone scaffold has attracted the great attention of organic and medicinal chemists to discover new synthetic routes [14][15][16][17][18] for the generation of novel acridones to be evaluated for biological activities and structure-activity relationships (SAR).…”

“…As part of an ongoing interest in developing new antiparasitic agents, we recently discovered a novel acridone chemotype that demonstrates efficacy against both liver and blood stage malaria. 11,12 Of the many conventional methods available for the synthesis of acridones from N-phenylanthranilic acid and ester derivatives, the most widely used is the strong acid catalyzed intramolecular Friedel-Cras cyclization in the presence of either sulfuric acid (H 2 SO 4 ), polyphosphoric acid (PPA), or Eaton's acid (Scheme 1). 12,19,20 In 2006, Nadaraj et al demonstrated the use of several other catalysts (e.g.…”

“…11,12 Of the many conventional methods available for the synthesis of acridones from N-phenylanthranilic acid and ester derivatives, the most widely used is the strong acid catalyzed intramolecular Friedel-Cras cyclization in the presence of either sulfuric acid (H 2 SO 4 ), polyphosphoric acid (PPA), or Eaton's acid (Scheme 1). 12,19,20 In 2006, Nadaraj et al demonstrated the use of several other catalysts (e.g. PTSA, ZnCl 2 , AlCl 3 and PPA) in the synthesis of acridones under microwave irradiation.…”

Tandem Access to Acridones and their Fused Derivatives: [1+2+3] Annulation of Isocyanides with Unsaturated Carbonyls

“…Acridones and their fused frameworks [1] are prominent moieties in many natural products, [2] anticancer drugs, [3] anti-malarials [4] and biomaterials. [2a,5] Moreover, the acridones are also served as useful building blocks for the construction of organic semiconductors, [6] dyestuffs and fluorescent labels.…”