compounds were evaluated for the obeyance of Lipinski parameters (RO5), topological polar surface area (TPSA), molar volume (MV), number of rotatable bonds (RB), absorption percentage (% ABS) and drug score.16 and 17 A series of N,5-disubstituted-1,3-thiazolidine-2,4-dione derivatives (3a–h, 4a–h) were designed and synthesized according to Scheme 1. The starting compound 1,3-thiazolidine-2,4-dione (1) and the N-substituted-1,3-thiazolidine-2,4-diones (2a, 2b) were prepared by literature method with modification.18 and 19 The compounds 2a, 2b were prepared by the reaction of methoxy phenacyl bromide/substituted benzyl halide with 1,3-thiazolidine-2,4-dione in ethanolic GDC0449 KOH. The initial potassium salt formation was ensured by the drop wise addition of KOH solution to the ethanolic thiazolidine-2,4-dione (1) and stirring at rt for 15 min, which on subsequent addition of methoxy phenacyl bromide/p-nitro benzyl bromide afforded N-substituted-1,3-thiazolidine-2,4-dione analogues (2a, 2b). The TLC support for qualitative analysis was utilized and the reaction was found completed after 6 h of reflux with stirring. The pure compounds were isolated by column chromatography. Modifications in the reaction conditions such as performing a single step reaction for the formation of potassium salt and the Perifosine subsequent N-alkylation rather than in two steps and controlled stirring before and after the addition of alkyl halide, influences the reaction
time and drastically decreased it to 6 h when compared with the literature method. 20 Further synthetic investigation as mentioned in Scheme 1 is performed with N-substituted-1,3-thiazolidine-2,4-diones (2a, 2b). Knoevenagel condensation of various aromatic aldehydes with N-sustituted-1,3-thiazolidine-2,4-diones afforded sixteen
N,5-disubstituted-1,3-thiazolidine-2,4-diones (3a–h and 4a–h). The carbanion formation, prerequisite for the knoevenagel condensation reaction is ensured by the use of piperidine as base, while removal of water is ensured by Dean–Stark apparatus.20 The compounds 4d, 4a, 3b and 3e were obtained with 92%, 87%, 85% and 83% yield (Table 1). The structures of the synthesized compounds were established based on spectral data analysis. The following observations are few among them: Aromatic CH stretching vibrations at 2841–3120 cm−1, the two ketones of the dione system were observed at 1602–1775 cm−1 these in the IR spectrum, appearance of –OH protons at δ 8.9–9.3, aromatic protons at δ 7.05–8.4, benzylidene ( CH) protons at δ 7.78–8.1, methoxy (–OCH3) protons at δ 3.54–3.83 and methyl (–CH3) protons at 2.9–3.0 in 1H NMR spectrum of the synthesized compounds. The absence of characteristic –NH peak of 1,3-thiazolidine-2,4-dione at 3200 cm−1 in IR spectra and a signal at δ 12 in 1H NMR confirmed the N-alkylation of 1,3-thiazolidine-2,4-dione. It was further evidenced by the appearance of molecular ion peak at m/z 265 and m/z 252 for compounds 2b and 2c respectively.