A SERIES OF PHOSPHORHYDRAZIDE (PHA) DERIVATIVES WITH THE (X=O,S) P-NHA-NHB-C(X=O,S) SKELETON (1-23) WERE SYNTHESIZED AND CHARACTERIZED BY 31P, 13C, 1H NMR AND FT-IR SPECTRAL TECHNIQUES. ALSO, THE CRYSTAL STRUCTURES OF COMPOUNDS 4 AND 21 WERE INVESTIGATED. THE GREATEST AND LOWEST 2JPNHΑ VALUES ARE OBSERVED FOR 1 (41.2 HZ) AND 13 (12.3 HZ) IN ORDER OF WITH THE (S)P-NHA-BHN-C(O) AND (O)P-NHA-BHN-C(S) SKELETONS, BECAUSE STABILIZATION ENERGIES FOR THE LP (XP)®S* (P-NA) INTERACTION FOR THE P=S MOEITY ARE LOWER THAN THE P=O MOIETY. THE INHIBITORY ACTIVITY OF PHAS WAS EVALUATED USING THE MODIFIED ELLMAN‘S METHOD IN CONTRAST CHOLINESTERASE (CHE) ENZYMES. DOCKING ANALYSIS DISCLOSED THAT THE HYDROGEN BONDS OCCURRED BETWEEN THE N-HA PROTON OF THE (S)P-NHA-NHB-C(S), (O)P-NHA-NHB-C(S) AND (O)P-NHA-NHB-C(O) MOIETY WAS WELL AS BETWEEN THE N-HB PROTON OF THE (S)P-NHA-NHB-C(O) MOIETY AND THE RECEPTOR SITE (GLY) OF ACHE ENZYME. PCA-QSAR INDICATED THAT THE CORRELATION COEFFICIENTS OF THE ELECTRONIC VARIABLES WERE DOMINANT COMPARING TO THE STRUCTURAL DESCRIPTORS. MLR-QSAR MODELS CLARIFIED THAT THE NET CHARGES OF N-HΑ NITROGEN ATOM CONTRIBUTE AS IMPORTANT ELECTRONIC FUNCTION IN THE INHIBITION OF ACHE. A HIGH INTERRELATIONSHIP WAS OBSERVED BETWEEN QN(A) AND QP (R=-0.686) IN THE CORRELATION MATRIX. THEREFORE, THE NH-P(X) MOIETY HAS VERY HIGHER INHIBITORY THAN THE NH-C(X) MOIETY.

INTRODUCTION: ONE OF THE STRATEGIES FOR TREATING ALZHEIMER’S DISEASE HAS BEEN TO ENHANCE CHOLINERGIC FUNCTION TO SUSTAIN OR PROLONG THE ACTION OF REMAINING ACETYLCHOLINE [1] USING CHOLINESTERASE INHIBITORS. ...