Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides, sulfonamides, ureas and thioureas

Abstract

We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolylderived sulfonamides 3-8 and 11-26, ureas 19-22, thioureas 23-26, and amides 27-54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of P. falciparum) and low resistance indices were obtained in most cases. Systematic variation of the side chain length and introduction of fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In particular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high antiplasmodial potency with a low resistance index and showed IC 50 's of 17.5 nM and 22.7 nM against HB3 and Dd2 parasites.

Relative to Quinine and Quinidine, Their 9-Epimers Exhibit Decreased Cytostatic Activity and Altered Heme Binding but Similar Cytocidal Activity versus Plasmodium falciparum

“…We thus tested for a possible correlation between inhibition and antiplasmodial activity using a series of CQ analogues that are structurally similar yet span a wide range of antiplasmodial IC 50 s and LD 50 s ( Fig. 1; see Table S1 in the supplemental material) (24,(41)(42)(43). These analogues also span the effective monobasic, dibasic, and tribasic character and thus diverge in calculated VARs (see Materials and Methods).…”

“…Synthesis and chemical characterization of CQ analogues 1 to 5 have been reported previously (24,(41)(42)(43). Compounds 6 to 9 were synthesized as described below.…”

“…Briefly, cultures were maintained under an atmosphere containing 5% O 2 , 5% CO 2 , 90% N 2 gaseous mix at 2% hematocrit and 1 to 2% parasitemia in RPMI 1640 supplemented with 10% type O-positive human serum, 25 mM HEPES (pH 7.4), 23 mM NaHCO 3 , 11 mM glucose, 0.75 mM hypoxanthine, and 20 g/liter gentamicin with regular medium changes every 48 h. Antiplasmodial cytocidal (LD 50 ) and cytostatic (IC 50 ) activities against the chloroquinesensitive (CQS) HB3 strain and CQR Dd2 strain were assessed. Cytostatic antiplasmodial activities have previously been reported for some drugs used in this study (24,(41)(42)(43), and additional activities were determined as described previously (47,48), with minor modifications.…”

Quinolines and structurally related heterocycles as antimalarials

“…Wolf et al reported in vitro antimalarial activities of the 4-amino-7-chloroquinolyl derived sulfonamides, ureas, thioureas, and amides [42]. Many of the analogues showed promising antimalarial activity and low resistance indices.…”

“…a relatively less explored approach. The disclosure of ferrochloroquine (FQ,42), in which the carbon chain of CQ is replaced by the hydrophobic ferrocenyl group has been a welcome addition to organometallic antimalarial drugs[69,70]. This compound has been shown to be superior to CQ in both in vitro and in vivo tests.…”