QSAR, Molecular modeling, Molecular docking and Preparation of Some N-substituted Acridinedione and Polyhydroquinoline Derivatives

Abstract

Quantitative Structure-activity relationship (QSAR) study was carried out using ACD/lab and MOE software’s, for developing a correlation between the structural properties of acridinedione and polyhydroquinoline derivatives (in which the 1,4- dihydropyridine is the basic molecule in their structure), and their anti-cancer activities. From this correlation, new chemical were designed, and their biological activities were predicted from their physicochemical descriptors by using multiple linear regression method. The QSAR models were considered to be good according to the acceptable statistical values obtained. (R= 0.993). Statistical parameters were also calculated for the two groups respectively. R=0.966 R2 =0.933 RMSE=0.03817 Q=0.9085 Q2 = 0.990 s= 0.013 F= 283.74 p= 0.004 R=0.9011 R2 = 0.812 RMSE=0.05156 Q= 0.7917 Q2 = 0.6267 s= 0.021 F= 34.511 p= 0.0001 1, 4-Dihydropyridines as analogues of Nicotineamide adenine Dinucleotide (NADH) coenzymes exhibit a wide range of biological activities, such as Calcium blocking, and today used in pharmacology. Acridines which possess the 1,4-dihydropyridine parent nucleus have interesting pharmaceutical properties such as a positive ion tropic effects promoting the eatery of Calcium to the intracellular space, and acridine-1,8-(2H,5H)- diones are known as laser dyes. Members of these class characterizes by having several common chemical and biological activities. Acridinediones were synthesized by the one-pot Hantzsch condensation of aromatic aldehydes, 5, 5-dimethyl-1, 3-cyclohexanedione (Dimedone) and aniline in refluxing. This method has then been extended to the four-component reaction of aromatic aldehydes, 5, 5-dimethyl-1, 3-cyclohexanedione (Dimedone) ethyl acetoacetate and ammonium acetate for the synthesis of polyhydroquinoline derivatives. Chapter one of this work covers a concise review of methods of synthesis of these class with their biological activities a alongside other topics. In chapter two from this study ten compounds derived from both acridinedione and polyhydroquinoline were prepared. The synthetic designing of these compounds was worked out through the suitable retro-synthetic analysis and the use of the disconnection approach. Cyclization was achieved through Hantzsch condensation followed by Michael type addition reaction mechanisms which sometimes catalyzed by CTAB in refluxing water was discussed in chapter three. The reaction course were monitored by TLC technique, recrystalization and TLC were used for purification purposes. The structures of the prepared compounds were elucidated by IR, UV, 1H-NMR and Mass Spectrometer. Molecular docking was also carried out so as to find out the binding affinity of target compounds with suitable protein that was obtained from the Protein Data Bank (PDB). The obtained spectroscopic data showed that the prepared compounds gave closed results.