This study aimed at evaluating the reactivity of L-Tryptophan (TRP) 1 towards various chemical reagents to produce new bi- and tri-heterocyclic systems providing basic pharmacological activities. Indol-3-yl hydroxyoxazol-2-yl acetonitrile derivatives 5 and 6, indol-3-yl-hydroxyoxazol-2-yl-1,2,4-triazine derivatives 8 and 9, indol-3-yl-hydroxyoxazol-2-yl-aminopyrazole derivatives 11a, b, and indol-3-yl-hydroxyoxazol-2-yl-aminoisoxazole derivative 12 were synthesized via straightforward and efficient methods. The structures were characterized by spectral data (IR, (1)H-NMR, (13)C-NMR, and MS) and the purity was ascertained by microanalysis. Also, this work was extended to study the potential role of the novel synthesized TRP derivatives 5, 6, 9, 11a, and 12 as antidepressant and sedative agents in comparison with TRP. All compounds showed significant antidepressant activity in the forced-swimming test at two doses (50 or 100 mg/kg). Also, all tested compounds (at 50 or 100 mg/kg) produced a significant decrease in locomotor activity of mice during a 30 min observation period. The most potent antidepressant and sedative effect was produced by the tri-heterocyclic compounds 9 and 12, followed by 11a and TRP.