Structure-activity relationship studies of phenylnitroethane analogues.

Ajiboye, Adebisi Oluwaseun (2013)



This study synthesized analogues of phenylnitroethane, determined their physico-chemical properties, evaluated the pharmacological potencies and investigated the correlation between their potencies and the physico-chemical parameters. This was with a view of optimizing the lead molecule - β-phenylnitroethane (BPNE) through the evaluation of synthetic analogues for the central nervous system activities. Derivatives of BPNE were prepared from the corresponding nitroalcohols by direct deoxygenation with triethylsilane and trifluoroacetic acid. The precursor nitroalcohols were obtained employing Henry reaction using tetramethylguanidine as a base. The starting reagents were the benzaldehyde derivatives which were initially protected by benzylation where phenolic. Intermediate and final products were purified by chromatography and identified by Nuclear Magnetic Resonance spectroscopy. The final nitroethanes and the intermediate nitroalcohols were evaluated for hypnotic effect assessed by ketamine-induced hypnosis, hypothermic effect evaluated by measuring variation in rectal temperature using rectal thermometer and anticonvulsant effect assessed by pentylene tetrazole (PTZ) - induced convulsions. Log P values were obtained using ALOGPS 2.1 applet from Virtual computational chemistry laboratory (VCCLAB). Correlation between log P and individual neuropharmacological activity was evaluated. Seven nitroalcohols and two analogues of BPNE were obtained in addition to the lead molecule (BPNE). Four nitroalcohols [1-phenyl-2-nitroethanol (BZA), 1-(4-methoxyphenyl)-2-nitroethanol (MBP), 1-(3,4,5-trimethoxyphenyl)-2-nitroethanol (MeOB3X) and 1-(3,4-methylenedioxyphenyl)-2-nitroethanol (POH)] and two nitroethanes [1-(3,4-dimethoxyphenyl)-2-nitroethane (DMNE) and 1-(4-benzyloxy-3-methoxyphenyl)-2-nitroethane (BVNE)] showed significant (P<0.05) decrease in sleep latency (SL) with BVNE [56.20 ± 2.47] showing superior activity to the lead molecule (BPNE) [74.60 ± 6.10]. Two nitroalcohols (MBP and POH) showed significant (P<0.05) prolongation of total sleeping time (TST) with MBP [3296.80 ± 280.79] showing the best activity among the test compounds while BPNE showed a superior TST of 4584.60 ± 249.06. None of the two test analogues of nitroethane exhibited significant (P˂ 0.05) effect on TST. Five nitroalcohols [BZA, POH, 1-(3,4-dimethoxyphenyl)-2-nitroethanol (DMP), 1-(4-benzyloxy-3-methoxyphenyl)-2-nitroethanol (BZV-ALC) and 1-(3, 4-dibenzyloxyphenyl)-2-nitroethanol (DBP)] and one nitroethane (BVNE) caused significant reduction in rectal temperature at 30 mins. Depression in the rectal temperatures for the active compounds at 60 mins post treatment were MBP (2.68 ± 0.23), DMP (2.50 ± 0.15) and DBP (2.08 ± 0.37); and that of BPNE was (1.96 ± 0.42) while that of the negative control (5% Tween 80) was 0.44 ± 0.23. BPNE showed 100% protection on the PTZ-induced convulsions at 100 mg/kg, i.p. while none of the test compounds showed any significant anticonvulsant activity. The study concluded that nitroalcohols with log P value less than 2.0 are likely to be hypnotically active and there is no correlation between log P, hypothermic and anticonvulsant effects. While the nitroethanes available are too few for quantitative correlation studies, the lead molecule was unique in its hypnotic and anticonvulsant activities.