Structure−Activity Relationship of Quinoline Derivatives as Potent and Selective α_2C-Adrenoceptor Antagonists

Abstract

Starting from two acridine compounds identified in a high-throughput screening campaign (1 and 2, Table 1), a series of 4-aminoquinolines was synthesized and tested for their properties on the human alpha(2)-adrenoceptor subtypes (alpha(2A), alpha(2B), and alpha(2C)). A number of compounds with good antagonist potencies against the alpha(2C)-adrenoceptor and excellent subtype selectivities over the other two subtypes were discovered. For example, (R)-{4-[4-(3,4-dimethylpiperazin-1-yl)phenylamino]quinolin-3-yl}methanol 6j had an antagonist potency of 8.5 nM against, and a subtype selectivity of more than 200-fold for, the alpha(2C)-adrenoceptor. Investigation of the structure-activity relationship identified a number of structural features, the most critical of which was an absolute need for a substituent in the 3-position of the quinoline ring. The 3-position on the piperazine ring was also found to play an appreciable role, as substitutions in that position exerted a significant and stereospecific beneficial effect on the alpha(2C)-adrenoceptor affinity and potency. Replacing the piperazine ring proved difficult, with 1,4-diazepanes representing the only viable alternative.

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

“…MV006172 was shown to have moderate activity against the liver stage of Plasmodium yoelii (30), and this compound was also found to bind to the recombinant human ␣-2C adrenergic receptor (51). MMV019555 is a dimeric molecule that was originally explored as an acetylcholinesterase inhibitor (52).…”

Discovery of Plasmodium vivaxN-Myristoyltransferase Inhibitors: Screening, Synthesis, and Structural Characterization of their Binding Mode

“…7 A number of potential substrates were tested, with Homo sapiens pp60 src (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) (GSNKSKPKDASQRRR-NH 2 ) being chosen as the most suitable substrate for the PvNMT assay, with apparent K m (K m app ) of 5.71 ± 0.6 μM in assay conditions. The compound collection was sourced by Medical Research Council Technology, largely from commercial suppliers.…”

Anti-tumoral activity of imidazoquines, a new class of antimalarials derived from primaquine

“…[1][2][3] Quinolines may have other relevant biological effects, such as the potent and selective antagonism to a 2C -adrenoreceptors of some 4-aminoquinolines with potential applications in the therapy of CNS disorders. 4 Recently, Strobl and co-workers found that the cinchona tree bark antimalarial quinidine inhibited growth of human breast tumor cells, 5 which prompted them to engage in the study of other anti-proliferative quinolines and to the proposal of four of such compounds as breast tumor cell differentiation agents. 6 Mahajan et al have also described new 7-chloroquinolyl thioureas structurally related to chloroquine as potential antimalarial and anticancer agents.…”

“…Modification of the primaquine's terminal primary amine, by insertion of either imidazolidin-4-one (3, 4) or dipeptide (6, 7) moieties generally had a detrimental effect on anti-tumoral activities, which was more pronounced for imidazolidin-4-one peptidomimetic structures (3,4) -acetyl group leads to activity loss, thus indicating that the primary amine from the Nterminal amino acid has a relevant role for the anti-tumoral activity of peptidomimetic imidazoquines as 3a. This is possibly a key structural requirement for activity against MCF-7 cells, as the compounds displaying lowest IC 50 values on this cell line, that is, primaquine (1), imidazoquine 3a and N-dipeptidylprimaquines 6, 7 all have an aliphatic primary amine whose acetylation leads to significant loss of activity (5 vs 1, 3b vs 3a).…”