Synthesis and in vitro and in vivo pharmacological evaluation of new 4-aminoquinoline-based compounds.

Abstract

A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitro. Pharmacokinetic studies on 3d and 3e in mice showed that they had moderate half-life (4-6 h) and low oral bioavailability. The front runner compound 3d exhibited moderate inhibition of the malaria parasite on P. berghei infected mice following oral administration (5 mg/kg), achieving reduction of parasitemia population by 47% on day 7.

• Authors: Matshawandile Tukulula, Mathew Njoroge, Efrem T Abay, Grace C Mugumbate, Lubbe Wiesner, Dale Taylor, Liezl Gibhard, Jennifer Norman, Kenneth J Swart, Jiri Gut, Philip J Rosenthal, Samuel Barteau, Judith Streckfuss, Jacques Kameni-Tcheudji, Kelly Chibale
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 4 Issue 12 Pg. 1198-202 (Dec 12 2013) ISSN: 1948-5875 [Print] United States
• PMID: 24900630 (Publication Type: Journal Article)