Recent publications have identified a number of novel quinoline and acridone compounds that appear to either reverse or evade the chloroquine-resistance mechanism in vitro, and which are considered to be promising leads for the development of new antimalarials (Burgess et al. J Med Chem 2006; 49:5623-5, October et al. Chem Med Chem 2008; 3:1649-53, and Kelly et al. Nature 2009; 459:270-3). The efficacy of these compounds against chloroquine-resistant strains is thought to be due to their ability to block mutant PfCRT or, alternatively, to the absence of an interaction with PfCRT, which would allow the drugs to escape the resistance mechanism altogether.
We are designing and evaluating novel quinoline-type drugs, 'reversed-quinolines’, and 'resistance-reversers' in collaboration with a number of different groups including Dr Russell Barrow (ANU), Prof Tim Egan (University of Cape Town), Prof David Peyton (Portland State University and DesignMedix, Inc), Dr Jane Kelly and Prof Michael Riscoe (Portland VA Medical Center), Dr Christine Hrycyna and Prof Jean Chmielewski (Purdue University), and Dr Sandra Gemma and Prof Giuseppe Campiani (NatSynDrugs, University of Siena). The objective of this work is to test the ability of a range of novel drugs, reversed-quinolines, and resistance-reversers to interact with mutant PfCRT, and to provide insights into the structural features important for these interactions.
Recent papers from this project:
- Hrycyna CA1, Summers RL1, Lehane AM1, Pires MM, Namanja H, Bohn K, Kuriakose J, Ferdig M, Henrich PP, Fidock DA, Kirk K, Chmielewski J2, and Martin RE2 (2014). Quinine dimers are potent inhibitors of thePlasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum. ACS Chemical Biology, 9:722-30 [1, 2: Equal contributions] Open access
- Deane KJ1, Summers RL1, Lehane AM, Martin RE2, and Barrow RA2 (2014). Chlorpheniramine analogues reverse chloroquine resistance in Plasmodium falciparum by inhibiting PfCRT. ACS Medicinal Chemistry Letters, 5: 576-81 [1, 2: Equal contributions]
- Gemma S, Camodeca C, Brindisi M, Brogi S, Kukreja G, Kunjir S, Gabellieri E, Lucantoni L, Habluetzel A, Taramelli D, Basilico N, Gualdani R, Tadini-Buoninsegni F, Bartolommei G, Moncelli MR, Martin RE, Summers RL, Lamponi S, Savini L, Fiorini I, Valoti M, Novellino E, Campiani G, and Butini S (2012). Mimicking the intramolecular hydrogen Bond: synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents. Journal of Medicinal Chemistry, 55: 10387-10404.
- Martin RE, Butterworth A, Gardiner D, Kirk K, McCarthy JS, and Skinner-Adams TS (2012). Saquinavir inhibits the malaria parasite's chloroquine resistance transporter. Antimicrobial Agents and Chemotherapy, 56: 2283-9. Open access
- Zishiri VK, Joshi MC, Hunter R, Chibale K, Smith PJ, Summers RL, Martin RE, and Egan TJ (2011). Quinoline antimalarials containing a dibemethin group are active against chloroquine-resistant Plasmodium falciparum and inhibit chloroquine transport via the P. falciparum chloroquine resistance transporter. Journal of Medicinal Chemistry, 54, 6956-68.