57181-84-7Relevant articles and documents
ICI 56,780 optimization: Structure-activity relationship studies of 7-(2-phenoxyethoxy)-4(1H)-quinolones with antimalarial activity
Maignan, Jordany R.,Lichorowic, Cynthia L.,Giarrusso, James,Blake, Lynn D.,Casandra, Debora,Mutka, Tina S.,LaCrue, Alexis N.,Burrows, Jeremy N.,Willis, Paul A.,Kyle, Dennis E.,Manetsch, Roman
, p. 6943 - 6960 (2016/08/05)
Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days.
Synthesis and in vitro pharmacology of substituted quinoline-2,4-dicarboxylic acids as inhibitors of vesicular glutamate transport
Carrigan, Christina N.,Bartlett, Richard D.,Esslinger, C. Sean,Cybulski, Kimberly A.,Tongcharoensirikul, Pakamas,Bridges, Richard J.,Thompson, Charles M.
, p. 2260 - 2276 (2007/10/03)
The vesicular glutamate transport (VGLUT) system selectively mediates the uptake of L-glutamate into synaptic vesicles. Uptake is linked to an H+-ATPase that provides coupling among ATP hydrolysis, an electrochemical proton gradient, and glutamate transport. Substituted quinoline-2,4-dicarboxylic acids (QDCs), prepared by condensation of dimethyl ketoglutaconate (DKG) with substituted anilines and subsequent hydrolysis, were investigated as potential VGLUT inhibitors in synaptic vesicles. A brief panel of substituted QDCs was previously reported (Carrigan et al. Bioorg. Med. Chem. Lett. 1999, 9, 2607-2612)1 and showed that certain substituents led to more potent competitive inhibitors of VGLUT. Using these compounds as leads, an expanded series of QDC analogues were prepared either by condensation of DKG with novel anilines or via aryl-coupling (Suzuki or Heck) to dimethyl 6-bromoquinolinedicarboxylate. From the panel of almost 50 substituted QDCs tested as inhibitors of the VGLUT system, the 6-PhCH=CH-QDC (Ki = 167 μM), 6-PhCH2CH2-QDC (Ki = 143 μM), 6-(4′-phenylstyryl)-QDC (Ki = 64 μM), and 6-biphenyl-4-yl-QDC (Ki=41 μM) were found to be the most potent blockers. A preliminary assessment of the key elements needed for binding to the VGLUT protein based on the structure-activity relationships for the panel of substituted QDCs is discussed herein. The substituted QDCs represent the first synthetically derived VGLUT inhibitors and are promising templates for the development of selective transporter inhibitors.
