Antiplasmodial Activity and Cytotoxicity of Bis-, Tris-, and Tetraquinolines with Linear or Cyclic Amino Linkers

Abstract

Bisquinoline heteroalkanediamines were structurally modified in order to study the effects of enhanced bulkiness and rigidity on both their activity on strains of Plasmodium falciparum expressing different degrees of chloroquine (CQ) resistance and their cytotoxicity toward mammalian cells. While cyclization yielded molecules of greater rigidity that were not more active than their linear counterparts, they were characterized by an absence of cytotoxicity. Alternatively, dimerization of these compounds led to tetraquinolines that are very potent for CQ-resistant strains and noncytotoxic.

Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

“…The design and synthesis of dimeric analogs of CQ that exploit the thermodynamic advantages imparted by polyvalency (11,12) has been previously studied in the context of malaria (13)(14)(15). The synthesis of heteroalkane-bridged bisquinolines did not produce sufficient antimalarial activity to warrant further investigation (14).…”

“…The synthesis of heteroalkane-bridged bisquinolines did not produce sufficient antimalarial activity to warrant further investigation (14). Subsequently, a series of tetraquinolines was reported with potent antimalarial properties (13), confirming that polyvalency could afford increased potency. Augmented cytotoxicity was observed in cancer cell lines when Akt inhibitors were combined with fluorinated quinolines (16), and CQ analogs with a piperazine connector had enhanced anticancer properties compared with CQ (17).…”

Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene-bis(methylene)-linked bis(+)-huprines

“…Huprine Y bears the 4-amino-7-chloroquinoline moiety, thought to be an antimalarial pharmacophore responsible for inhibition of heme dimerization. 20,34 Since dimerization of other 4-aminoquinoline compounds increased antiplasmodial potency and/or overcame the chloroquine resistance mechanism, [26][27][28][29] we hypothesized that dimerization of huprine Y to bis-huprines (+)-2a-e might also enhance activity. However, no noticeably increased antiplasmodial potency was observed for the dimeric compounds, which exhibited IC 50 values > 5 µg/mL (i.e.…”

“…25 This approach has proven successful for dimers of 4-aminoquinolines, in which the two constituting units were connected through linkers of different length or containing different functional groups. [26][27][28][29] Here, we report the synthesis of dimers of huprine Y, in which the two huprine moieties have been connected through oligomethylene linkers of different length, or with a p-phenylenebis(methylene) tether. To this end, enantiopure (+)-(7R,11R)-huprine Y [(7R,11R)-1, Scheme 1], the least active enantiomer in terms of acetylcholinesterase (AChE) inhibition activity, [30][31][32] has been used.…”

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

“…30 Next, we turned our attention to the molecular dimerization of huprine Y because this approach had been successfully applied to other 4-aminoquinoline derivatives to overcome drug resistance. [32][33][34][35][36] One of the most interesting huprine dimers was the novel dodecamethylene-linked bis(4-aminoquinoline) compound 2 ( Fig. 1), which tripled the potency and selectivity of the parent huprine Y against T. brucei but remained inactive against P. falciparum.…”