Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity

Abstract

Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. Inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers but likely it is not their main biological target within Trypanosoma brucei. Regarding their antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis and cerebral malaria. Future optimization should mainly focus on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.

Synthesis and biological evaluation of N -cyanoalkyl-, N -aminoalkyl-, and N -guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents

“…We recently found that both homodimerization and heterodimerization of the 4-aminoquinoline derivative huprine Y results in increased potency against T. brucei and improved selectivity over mammalian cells relative to the parent compound,36, 37 albeit at the expense of increasing lipophilicity and molecular weight. In this current paper, we have explored the effect on antitrypanosomal activity of the introduction of a side chain, featuring a terminal cyano, amino, or guanidino group, at the primary amino group of huprine Y or the simpler structurally related tacrine or 6-chlorotacrine, as an alternative approach to improve the antitrypanosomal profile.…”

“…Interestingly, we have found that homodimerization of huprine Y (as in compound 2 , 36 Fig. 1) and heterodimerization with the 4-aminoquinoline derivative tacrine (as in compound 3 , 37 Fig. 1) also results in up to 3-fold increased potency and selectivity against T. brucei .…”

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

“…The majority of heteronuclear quinoline dimers 31 showed considerable activity against CQR K1 strain with IC 50 in nanomolar level, and half of them (IC 50 : 350‐470 nM) were more active than CQ (IC 50 : 930 nM) . Compared with the unsubstituted analogs, hybrids with ‐Cl at R position displayed lower activity.…”

Challenges in the chemotherapy of Chagas disease: Looking for possibilities related to the differences and similarities between the parasite and host

“…Since then, several TR inhibitors have been discovered by using the models of Zhang and Jacoby, especially the aminoacridine (7), a higher homolog of (6), as described by Bonse et al[ 51 ], and a pyridazine (8) and a carbazole (9) described by Horvath[ 52 ]. More recently, the inhibitory activity of more potent derivatives such as thioridazine (10) and aminoquinoline (11) was described by Lo Presti et al[ 53 ] and Sola et al[ 54 ], respectively.…”