Design of new potent and selective secretory phospholipase A2 inhibitors. Part 5: Synthesis and biological activity of 1-alkyl-4-[4,5-dihydro-1,2,4-[4H]-oxadiazol-5-one-3-ylmethylbenz-4′-yl(oyl)] piperazines

Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities

“…The BTCP fragment was synthesized starting from an optimized procedure originally developed by Costa et al [28,29] Cyclohexanone (28) tane yielded inhibitor 32, which was previously described as the BTCP analogue with the highest TR affinity by Patterson et al [16] Treatment of amine 31 with dichloride 33, which was generated in situ from bis-(2-hydroxyethyl)-propyn-2-ylamine [30] yielded alkyne 34, whereas treatment with dichloride 35 gave tosylamine 36, which, upon deprotection, afforded piperazine 37.…”

Design of new potent and selective secretory phospholipase A2 inhibitors. 6-Synthesis, structure–activity relationships and molecular modelling of 1-substituted-4-[4,5-dihydro-1,2,4-(4H)-oxadiazol-5-one-3-yl(methyl)]-functionalized aryl piperazin/one/dione derivatives

“…The log P values were calculated using the Rekker's hydrophobic fragmental constants method. 49 Our previous work 32 showed that introduction of a piperazine ring (compound II) in the structure of compound I did not affect neither the inhibitory effect against GIIA sPLA 2 with IC 50 of 2.2 and 3.4 lM, respectively, nor the selectivity GIIA/GIB (Table 1). In addition, it offered the ability of protonation at physiological pH then lowering the lipophilicity supposed to enhance biodistribution.…”

“…32 Diphenylmethylpiperazine was treated with the appropriate acid chloride to give the 4-acyl-1-diphenylmethylpiperazines 1b,d which were deprotected by hydrogenolysis into the 1-acylpiperazines 2b,d. The carbamates 4a,c were obtained after preparing first the carbonates 3a,c by esterification of the corresponding primary alcohol by phenyl chloroformate followed by treatment with an excess of piperazine.…”

“…In the same manner, introduction of the urea function was obtained by addition of an excess of piperazine to the chosen alkylisocyanate to give 5a,c. As for alkylpiperazines 6a,c, 7a and 8a, they were prepared as described by Boukli et al 32 starting from the corresponding 1-alkylbromide and either piperazine or mono or dimethyl piperazines.…”

“…32 Here we report a SAR study by examining the influence of structural modifications of II and III on inhibiting activity and selectivity towards GIIA versus GIB sPLA 2 s. They included replacing either one nitrogen or both by different functions as amide, carbamate, urea and/ or branching directly an alkyloxyphenyl group, keeping a long C 10 -C 18 alkyl chain. We also diminished flexibility of piperazine ring by branching one (or two) methyl group(s) on one (or two) carbon atom(s) of this cycle or replacing one (or two) methylene(s) by one (or two) carbonyl(s) leading to substituted piperazinones and piperazinediones.…”