SYNTHESIS OF PHARMACOLOGICALLY ACTIVE NITROGEN HETEROCYCES

North Carolina Central University, Durham NC

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Abstract

Our previous investigations have demonstrated that members of several classes of organic heterocyclic compounds have potent pharmacological activities as antineoplastic, cytotoxic, hypolipidemic, and antiinflammatory agents. Additional derivatives of several of these classes will be synthesized in order to complete structure activity relationship (SAR) for these classes. Derivatives of several new and/or previously unstudied classes of compounds will also be synthesized. Computer assisted drug design (CADD) will be used as a guide in the selection of derivatives to be prepared. SYBYL 6.3 molecular modeling software with comparative Molecular Field Analysis (SoMFA will be utilized for the CADD studies. The pharmacological activity testing will be performed by Dr. Iris H. Hall at the School of Pharmacy, University of North Carolina at Chapel Hill. In addition to SAR evaluations, mode of action, LD50 values, and pharmacokinetics will be determined on the most potent agents in each chemical class. A series of 3,5-isoxazolidinediones and 3,5-pyrozolidinediones will be synthesized by the condensation of substituted malonyl chlorides and esters with hydroxamic acids, hydroxyl amines, and hydrazine, respectively. The 3,5-pyrozolidinediones will be mono and disubstitued with acylalkyl groups at positions 1 and 2. In a similar manner of series of 1,2,4-triazolidine-3,5-diones will be mono and disubstitued at positions 1 and 2 with acylalkyl groups. Derivatives of 1,5- diazabicyclo[3.1.0]hexane2,4-dione will be synthesized by the reaction of 1-pyrazoline-3,5-diones and acyl substituted dizoalkanes and by the condensation of 1,2 unsubstitued diazridines and malonyl chlorides. Other classes of compounds to be synthesized include 1-alkylideneamino- 2,4azetidinediones, 2-alkylideneaminophthalimides, and other five- membered nitrogen heterocyclic compounds containing one or two ring carbonyl groups