4,9‐Diaminoacridines and 4‐Aminoacridines as Dual‐Stage Antiplasmodial Hits

Abstract

Multi‐stage drugs have been prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. Herein, we disclose two novel acridine‐based families of compounds that combine the structural features of primaquine and chloroquine. Compounds prepared and studied thus far retained the in vitro activity displayed by the parent drugs against the erythrocytic stages of chloroquine‐sensitive and ‐resistant Plasmodium falciparum strains, and against the hepatic stages of Plasmodium berghei, hence acting as dual‐stage antiplasmodial hits.

Improved synthesis of antiplasmodial 4-aminoacridines and 4,9-diaminoacridines

“…Our research group makes no exception to this rule, very much driven by our long-term interest in antiinfective agents, including antimalarials inspired in mepacrine. [14][15][16][17][33][34][35][36][37][38] This led us to advance, in recent years, new 4aminoacridines (15) and 4,9-diaminoacridines (10) as multi-stage antiplasmodial hits. 15,16 Although we were successful in addressing their quite challenging synthesis, the overall modest yields obtained as well as harsh and/or time-consuming procedures involved prompted us to work on the optimization of the synthetic routes.…”

“…[14][15][16][17][33][34][35][36][37][38] This led us to advance, in recent years, new 4aminoacridines (15) and 4,9-diaminoacridines (10) as multi-stage antiplasmodial hits. 15,16 Although we were successful in addressing their quite challenging synthesis, the overall modest yields obtained as well as harsh and/or time-consuming procedures involved prompted us to work on the optimization of the synthetic routes. The efforts undertaken are herein described and allowed us to make signicant progress on several parts of the overall synthesis scheme.…”

“…13 Based on the well-known therapeutic potential of aminoacridines, [14][15][16][17] our research group recently developed two unprecedented synthesis routes towards 4,9-diaminoacridines and 4-aminoacridines (Scheme 1). 15,16 These routes comprise two main parts: (a) production of the 6,9dichloro-2-methoxy-4-nitroacridine precursor common to both 4,9-diaminoacridine and 4-aminoacridine target families (Scheme 1, part A), and (b) further modications in C-9 and/or C-4 positions of the acridine ring (Scheme 1, part B). 15,16 Both are extensive and laborious synthetic routes that involve several steps featuring harsh reactional conditions and low yields.…”

Acridine-Based Antimalarials—From the Very First Synthetic Antimalarial to Recent Developments

“…Recently, Fonte et al developed QN derivatives through the introduction of a like PQ -side chain in position 4 of the acridine ring ( Figure 10 ) towards multi-stage antimalarial drugs [ 21 ]. After the establishment of the synthetic route of these derivatives [ 22 ], the series of three compounds, with different side-chain length, were evaluated for their antimalarial activity against CQS 3D7 and CQR Pf W1 strains, and the hepatic stages of P. berghei .…”

“…Regarding liver-stage activity, compound 16a was significantly active at 10 μM (IC 50 = 11.02 µM), although the other derivatives were highly cytotoxic towards Huh-7 cells at this concentration. Remarkably, none of the compounds was hemolytic up to 10 µM [ 21 ].…”