Design and synthesis of 3-[(7-chloro-1-oxidoquinolin-4-ylamino)alkyl]-1,3-thiazolidin-4-ones as antimalarial agents

Figures & data

Figure 1.  Some lead molecules of 4-aminoquinoline derived antimalarials developed from this laboratory.

Scheme 1.  Synthesis of quinoline N^ω oxide derived thiazolidin-4-ones. Reagents and conditions: (a) Glacial Acetic acid/ H₂O₂, 70–80ºC for 12 h (b) Diamino alkane, ethanol reflux for 6–8 h; (c) RCHO, Mercapto acetic acid, Toluene reflux 18–24 h.

Table 1.  Biological and biophysical data of the compounds (3–14).

Comp. No	MIC^a (μM)	Log K^b	IC50^c (μM)	Log P^d	pKa1^d
3	4.21	4.75 ± 0.02	0.57 ± 0.11	0.23	2.41
4	3.97	4.79 ± 0.02	0.59 ± 0.09	0.58	2.54
5	3.76	5.00 ± 0.02	0.56 ± 0.09	1.09	2.93
6	3.18	4.29 ± 0.03	0.65 ± 0.09	0.25	2.63
7	2.30	5.14 ± 0.01	0.56 ± 0.06	3.18	2.63
8	0.27	5.12 ± 0.02	0.35 ± 0.04	3.82	2.63
9	2.96	4.32 ± 0.04	0.52 ± 0.13	0.61	2.63
10	0.28	5.19 ± 0.05	0.36 ± 0.07	3.54	2.63
11	0.52	5.22 ± 0.01	0.43 ± 0.05	4.18	2.63
12	2.84	4.38 ± 0.06	0.57 ± 0.13	1.12	2.93
13	4.04	5.24 ± 0.04	0.62 ± 0.21	4.05	2.93
14	4.32	5.35 ± 0.01	0.65 ± 0.19	4.69	2.93
CQ	0.39	5.52 ± 0.02	0.40 ± 0.10	4.27	8.41

^aMIC = Minimum inhibiting concentration for the development of the ring stage parasite into the schizont stage during 40-h incubation. ^b1:1 (compound: Haematin) complex formation in 40% aqueous DMSO, 20 mM HEPES buffer, pH 7.5 at 25°C (data are expressed as means ± SD from at least three different experiments in duplicate). ^cThe IC₅₀ represents the micromolar equivalents of test compounds, relative to hemin, required to inhibit β-haematin formation by 50% (data are expressed as means ± SD from at least three different experiments in duplicate). ^dLog P and pKa values are calculated by Pallas software.

Table 2.  In vivo antimalarial activity data of the compounds (8, 10, 11) against N-67 strain of P. yoelii in Swice mice.

C. No	% Suppression on day 4^a	Mean survival time^b (MST in days) ± SE
8	56.76	14.42 ± 0.59
10	59.49	14.22 ± 1.11
11	48.23	13.43 ± 0.24
CQ	99.99	18.00 ± 1.53
Control	—	10.11 ± 0.71

^aPercent suppression = [(C–T)/C] × 100; where C = parasitaemia in control group, and T = parasitaemia in treated group. ^bMST calculated for the mice which died during 28 day observation period and the mice which survived beyond 28 day are excluded.