The Evolution of Pleconaril: Modified O-Alkyl Linker Analogs Have Biological Activity towards Coxsackievirus B3 Nancy

Figures

• 

  Figure 1. The Evolution of Pleconaril.

• 

  Scheme 1. Synthesis of 3-(3-methyl-4-((3-(3-substitutedisoxazol-5-yl)propyl)thio)phenyl)-5-(trifluoromethyl)-1,2,4-oxadiazoles 6a,b and 7. Reagents and conditions: (a) 5-chloro-1-pentyne, K2CO3, KI, NMP, 65 °C; (b) NH2OH·HCl, K2CO3, EtOHabs, reflux; (c) (CF3CO)2O, pyridine, 80–90 °C; (d) 2-chloro-2-(hydroxyimino)acetic acid ethyl ester 5, Et3N, DMF, 80–90 °C; (e) acetaldoxime, N-chlorosuccinimide, pyridinecat, Et3N, DMF, 80–90 °C; (f) dimethylamine solution 17 wt.% in dioxane, 70–80 °C.

• 

  Scheme 2. Synthesis of 2-methyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl ester of 3-(3-substituted isoxazol-5-yl)propionic acids 12a,b. Reagents and conditions: (a) NH2OH·HCl, K2CO3, EtOHabs, reflux; (b) (CF3CO)2O, pyridine, 80–90 °C; (c) 4-pentynoic acid, DCC, pyridine, rt; (d) 2-chloro-2-(hydroxyimino)acetic acid ethyl ester 5, Et3N, DMF, 80–90 °C; (e) acetaldoxime, N-chlorosuccinimide, pyridinecat, Et3N, DMF, 80–90 °C.

• 

  Scheme 3. Synthesis of 2-methyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenylamide of 3-(3-substituted isoxazol-5-yl)propionic acids 20a,b and 21. Reagents and conditions: (a) Boc2O, 85 °C; (b) NH2OH·HCl, K2CO3, EtOHabs, reflux; (c) (CF3CO)2O, pyridine, 80–90 °C; (d) CF3COOH, DCM, rt; (e) 4-pentynoic acid, EDCl, DMAP, DCM, rt; (f) 2-chloro-2-(hydroxyimino)acetic acid ethyl ester 5, Et3N, DMF, 80–90 °C; (g) acetaldoxime, N-chlorosuccinimide, pyridinecat, Et3N, DMF, 80–90 °C; (h) dimethylamine solution 17 wt.% in dioxane, 70–80 °C.

• 

  Scheme 4. Synthesis of piperazine derivatives 28a,b. (a) ethyl 5-chloroisoxazole-3-carboxylate 23 or 5-(chloromethyl)-3-methylisoxazole 24, K2CO3, acetonitrile, reflux; (b) dimethylamine solution 33 wt.% in H2O, EtOH; (c) NH2OH·HCl, K2CO3, EtOHabs, reflux; (d) (CF3CO)2O, pyridine, 85 °C.

• 

  Scheme 5. Synthesis of piperazine derivatives 35a,b, 28c,d. (a) Ac2O, 65 °C; (b) CuCN, NMP, 150 °C; (c) NH2OH·HCl, K2CO3, EtOHabs, reflux; (d) (CF3CO)2O, pyridine, 80–90 °C; (e) HCl, EtOH; (f) 3-phenylisoxazole-5-carboxylic acid or 5-methyl-3-phenylisoxazole-4-carboxylic acid, EDC, DMAP, DCM, rt; (g) 5-chloroisoxazole-3-carboxylate 23, K2CO3, acetonitrile, reflux; (h) propargyl bromide, K2CO3, KI, acetonitrile, 50 °C; (i) 2-chloro-2-(hydroxyimino)acetic acid methyl ester 36, Et3N, DMF, 80–90 °C.

• 

  Figure 2. Cytotoxicity and anticoxsackievirus B3 activity of 6b (A), 21 (B), and 28a (C): logistic curves for cell viability (MTT assay) and relative viral titer (virus yield reduction assay).