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  • Tacrine amino tetrahydroacridine I Fig was the first AChEI

    2019-08-22

    Tacrine (9-amino-1,2,3,4-tetrahydroacridine) (I, Fig. 1) was the first AChEI to be approved by the Food and Drug Administration (FDA) for the treatment of AD [25], [26], [27], [28]. However, despite its good AChE inhibitory activity, tacrine was far from ideal due to its low bioavailability and short half-life. Furthermore, frequent administration of tacrine was found to be associated with significant hepatotoxicity [29], [30]. Accordingly, several structural modifications were performed on tacrine aiming at producing potent AChEIs (equivalent to or more potent than tacrine) with minimum hepatotoxic side effects to provide clinically advantageous drugs [5]. Among the accomplished structural modifications, introduction of a chloro substitution to the phenyl ring of tacrine resulted into a group of chlorinated tetrahydroacridines (THA) (II, Fig. 1) showing high AChE inhibitory activity [31], [32]. One other successful structural modification which was affected in our laboratories, was the design and synthesis of a group of 3-cyano-2-substituted tetrahydroquinolines having a phenyl ring at the 4-position (III, Fig. 1). Structure-activity relationship (SAR) studies of these compounds indicated that the presence of a chloro substituent at the 2-position of the pyridine ring resulted in a lead raas inhibitors that was more potent AChEI and less hepatotoxic than tacrine [1], [5]. Furthermore, studying the significance of the chloro substitution in tacrine analogs, Ragab et al. have previously synthesized two series of 4-phenyltetrahydroquinolines (IV; X  = H, Cl, Fig. 1) and evaluated their anti-cholinesterase activity and hepatotoxicity. The chlorinated compounds (IV; X  = Cl) showed higher AChE inhibitory activity and lower hepatotoxicity relative to the unchlorinated analogs (IV; X  = H) [5]. Correlating all the previously mentioned results, it was obvious that the presence of a chloro group on any of the aryl rings, whether pyridyl or phenyl, present in the synthesized tetrahydroquinolines (THQ) resulted in potent AChEIs with lower hepatotoxicity [5]. Further investigation of the synthesized chlorinated THQ compounds (IV where X = Cl) revealed that nature of the substituent at the 2-position was found to possess great influence on the AChE inhibitory activity and the hepatotoxicity of the products. Presence of an amino group, whether free or mono substituted, at the 2-position (V; R1 = alkyl and R2 = H, Fig. 2) resulted into compounds having the highest AChE inhibitory activity and least hepatotoxicity. However, the introduction of a second alkyl substituent on the 2-amino group (V; R1 = R2 = alkyl, Fig. 2) totally abolished the activity. Furthermore, fusing the pyridine ring to a pyrazolo nucleus (VI, Fig. 2) resulted in a promising activity [5]. In addition, in a trial to improve AChE activity and decrease hepatotoxicity, Reddy et al. introduced an amide moiety in the form of acidhydrazide at the 2-position of tacrine (VII, Fig. 2). The produced compound was found to be totally safe implying that the introduction of an amide group might be beneficial [33]. As an investment of the aforementioned findings, a novel group of chlorinated-2-amino-THQ derivatives with various functionalities and/or fused to different heterocyclic ring systems (VIII and IX, Fig. 3) was synthesized and evaluated for their AChE inhibitory activity and hepatotoxicity aiming at discovering potential potent AChEIs with lower (if any) hepatotoxicity than tacrine. The substitution pattern of the synthesized compounds was carefully chosen so as to examine the effect of different N-substituents at the 2-position having various electronic and lipophilic characters (VIII, Fig. 3). Furthermore, the effect of introduction of an amide group at the 2- and 3-positions of the synthesized analogs has been investigated. In addition, in case of fused heterocycles (IX, Fig. 3), it was targeted to study how increasing the size of the ring fused to the pyridine ring; a pyrimidine rather than a pyrazole, would affect the biological results of the synthesized compounds.