Incorporation of a 3-(2,2,2-Trifluoroethyl)-γ-hydroxy-γ-lactam Motif in the Side Chain of 4-Aminoquinolines. Syntheses and Antimalarial Activities

Abstract

In this paper we report the synthesis and antimalarial properties of two series of fluoroalkylated γ-lactams derived from 4-aminoquinoline as potent chemotherapeutic agents for malaria treatment. These molecules obtained in several steps resulted in the identification of very potent structures with in vitro activity against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) in the range of 19-50 nM with resistance indices in the range of 1.0-2.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81, 84, and 87) that are representative of the two series of compounds did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells up to a concentration of 100 μM. The most promising compounds (82 and 84) showed significant IC₅₀ values close to 26 and 19 nM against the chloroquino-sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our preliminary data indicate that this class of structures contains promising candidates for further study.

Synthesis and SAR studies of novel 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1H)‐one derivatives for anticancer activity

“…Among various nitrogen-containing fused heterocyclic skeletons, quinoline and quinolone structures are important components prevalent in a vast array of biological systems. Compounds with a quinoline nucleus exhibit various pharmacological properties, including antioxidant (Chung and Woo, 2001;Zhang et al, 2013), anti-inflammatory (Baba et al, 1996;Mukherjee and Pal, 2013), antibacterial (Cheng et al, 2013), anti-human immunodeficiency virus (Freeman et al, 2004;Hopkins et al, 2004), antimalarial (Cornut et al, 2013;Pandey et al, 2013), antituberculosis (Lilienkampf et al, 2009), anti-Alzheimer's disease (Fiorito et al, 2013), anticancer (Wang et al, 2011;Abonia et al, 2012;Chan et al, 2012) activities. Accordingly, Solomon and Lee described quinolinecontaining subunits as 'privileged structures' for drug development (Solomon and Lee, 2011).…”

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

“…The γ‐hydroxy‐γ‐lactam‐quinoline hybrids 106 (IC 50 : 43‐800 nM) and 107 (IC 50 : 56‐667 nM) displayed considerable activity against CQS 3D7 and CQR W2 strains of P falciparum , and a significant part of them was more potent than CQ (IC 50 : 750 nM) against CQR W2 strain . Amino‐containing linker was favorable to the activity when compared with alkyl linker, and chloro at C‐7 position of quinoline moiety was indispensable for the high activity.…”

“…For hybrids 106 , installation of trifluoroacetyl onto C‐3 position (R 2 ) of quinoline motif led to the loss of activity, and hybrids with thioether at R 3 position showed higher activity than the corresponding sulphone analogs. For hybrids 107 , hybrids with aromatic ring at R 1 position displayed better activity than the methyl analogs . Among them, eight hybrids with IC 50 less than 100 nM were comparable to CQ (IC 50 : 30 nM) against CQS 3D7 strain, and greater than 7.5‐fold more potent than CQ (IC 50 : 750 nM) against CQR W2 strain.…”

“…Further study indicated that citric acid salt form could boost up the activity to some extent. For example, the citric acid salt form of hybrids 106a (IC 50 : 19 and 42 nM) and 107a (IC 50 : 26 and 49 nM) were highly active against CQS 3D7 and CQR W2 strains of P falciparum …”

Diastereoselective radical addition to γ-alkyl-α-methylene-γ-butyrolactams and the synthesis of a chiral pyroglutamic acid derivative

“…γ-Lactams exist in many natural products and biologically active compounds and are one of the most important classes of compounds for drug discovery [1–3]. Substituted γ-lactams, in particular, have potential application in drug synthesis, but the development of stereoselective synthesis of chiral γ-lactams remains a challenge [4–5].…”