Structure-Activity Relationships and Antiplasmodial Potencies of Novel 3,4-Disubstituted 1,2,5-Oxadiazoles

Abstract

The 4-substituted 3-amino-1,2,5-oxadiazole 1 from the Malaria Box Project of the Medicines for Malaria Venture foundation shows very promising selectivity and in vitro activity against Plasmodium falciparum. Within the first series of new compounds, various 3-acylamino analogs were prepared. This paper now focuses on the investigation of the importance of the aromatic substituent in ring position 4. A number of new structure-activity relationships were elaborated, showing that antiplasmodial activity and selectivity strongly depend on the substitution pattern of the 4-phenyl moiety. In addition, physicochemical parameters relevant for drug development were calculated (logP and ligand efficiency) or determined experimentally (CYP3A4-inhibition and aqueous solubility). N-[4-(3-ethoxy-4-methoxyphenyl)-1,2,5-oxadiazol-3-yl]-3-methylbenzamide 51 showed high in vitro activity against the chloroquine-sensitive strain NF54 of P. falciparum (PfNF54 IC₅₀ = 0.034 µM), resulting in a very promising selectivity index of 1526.

Keywords: 1,2,5-oxadiazoles; CYP3A4-inhibition; Plasmodium falciparum; antimalarial; solubility.

Figure 1

Structure–activity relationships of the lead compound 1 and promising compounds from the first series of derivatives [14].

Figure 2

Preparation of compounds 6, 7, 8 and 21. Reagents and conditions: (a) NH₂OH x HCl, NaHCO₃, water, methanol, 100 °C, 2–3 h; (b) N-chlorosuccinimide, dry dimethylformamide, rt, 1–24 h; (c) potassium cyanide, diethyl ether, water, rt, 24 h or potassium cyanide, ethyl acetate, water, 5–10 °C, 30 min; (d) NH₂OH × HCl, NaHCO₃, water, methanol, 100 °C, 24 h; (e) 2N NaOH, 120 °C, 24 h or anhydrous sodium acetate, dry ethanol, 100 °C, 120–192 h; (f) H₂SO₄ 98%, HNO₃ 67%, rt, 1 h; (g) Na, dry ethanol, isoamyl nitrite, rt, 24 h.

Figure 3

Preparation of compounds 25 and 26. Reagents and conditions: (a) NaBH₄, dry methanol, rt, 1 h; (b) (1) dry dichloromethane, 0 °C; (2) thionyl chloride, rt, 24 h; (c) (1) dry dimethylformamide, potassium cyanide, 100 °C, 2 h; (2) potassium cyanide, 100 °C, 2 h; (d) Na, dry ethanol, isoamyl nitrite, rt, 24 h; (e) NH₂OH × HCl, NaHCO₃, water, methanol, 100 °C, 24 h; (f) 2N NaOH, 120 °C, 24 h.

Figure 4

Preparation of compounds 37–54. Reagents and conditions: (a) (1) NaH, dry dimethylformamide, aminofurazan, 0 °C, 20 min; (2) benzoyl chloride, dry dimethylformamide, 60 °C, 24 h (compounds 37 and 41); or (1) NaH, dry dimethylformamide, aminofurazan, 0 °C, 20 min; (2) m-toluoyl chloride, dry dimethylformamide, 60 °C, 24–48 h (compounds 38, 42, 47, 49, 51 and 52); or (1) NaH, dry dimethylformamide, aminofurazan, 0 °C, 20 min; (2) 3-fluorobenzoyl chloride, dry dimethylformamide, 60 °C, 24 h (compounds 39, 43, 45 and 46); or (1) NaH, dry dimethylformamide, aminofurazan, 0 °C, 20 min; (2) 3-(trifluoromethyl)benzoyl chloride, dry dimethylformamide, 60 °C, 24 h (compounds 40, 44, 48 and 50; or (1) 3-chloro-4-methoxybenzoic acid, N-hydroxy succinimide, DCC, dry tetrahydrofuran, rt, 24 h; (2) dry dimethylformamide, rt, 15 min; (3) NaH, dry dimethylformamide, aminofurazan, 0 °C, 20 min; (4) N-(aroyloxy)succinimide, dry dimethylformamide, 60 °C, 24 h (compounds 53 and 54).

Figure 5

Preparation of compounds 55–63. Reagents and conditions: (a) tin powder, 6N HCl, ethanol, 70 °C, 1 h.