DESIGN, SYNTHESIS AND ANTIDEPRESSANT ACTIVITY OF SOME N2-SUBSTITUTED NALIDIXIC ACID HYDRAZIDES AND THEIR CYCLIZED ANALOGUES

Abstract

A series of N2-substituted nalidixic acid hydrazides 7-26 and some of their rigid analogues 29-31 in which the hydrazinocarbonyl moiety has been replaced by the corresponding 1,3,4-oxadiazole nucleus were synthesized as potential antidepressant agents. The preparation of the aforementioned compounds was achieved by reaction of nalidixic acid hydrazine 6 with the appropriate carbonyl compound or isothiocyanate derivative to afford the corresponding N-alkylidenes 7-11; N-arylidenes 12-26 or the thiocarbamoylhydrazinocarbonyl derivatives 27 and 28 respectively. Cyclodesulfurization of the latter derivatives yielded the corresponding 5-substituted amino-1,3,4-oxadiazoles 29 and 30. the unsubstituted 5-amino-1,3,4-oxadiazol-2-yl derivative 31 was synthesized by interaction of the hydrazide 6 with cyanogens bromide. The structures of the synthesized compounds were confirmed by IR; 1H-NMR and MS and their purity as assessed by TLC and elemental analyses. Eleven of the synthesized compounds and isocarboxazide as a reference drug were tested at three dose levels (0.5; 1.0 and 1.5 mg/kg) for antidepressant activity in mice. Reduction in the duration of immobility in forced swimming test was taken as a measure for antidepressant activity. Seven of the tested substituted compounds and the unsubstituted hydrazide 6 exhibited highly significant difference from the control group at a dose level of 1.5 mg/kg. The acetophenonylidene derivative 18 showed antidepressant activity comparable to that of the reference drug. The rigid substituted hydrazide analogues represented by compound 29 were found to be inactive at the lower dose level and showed moderately significant difference than the control group at the higher dose level. This indicates that, cyclization of the hydrazide moiety to the corresponding 1,3,4-oxadiazole derivatives greatly reduced the antidepressant activity.