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  • Furthermore in silico physicochemical characters and pharmac

    2020-09-03

    Furthermore, in silico physicochemical characters and pharmacokinetic parameters for the synthesized compounds were predicted using dedicated computer software [34], [35], [36] to ensure successful in vivo therapeutic activity. Practical logP testing was performed and compared to the theoretical values obtained. Finally, a docking study of glycerophosphate 7 (the most in vitro active compound) was performed and its binding mode was compared to that of tacrine.
    Results and discussion
    Conclusion Due to the hepatotoxicity associated with the use of tacrine as AChEI in the treatment of AD, this study portrays the synthesis of fifteen chlorinated tetrahydroquinolines to serve as tacrine analogs with lower hepatotoxicity. The in vitro testing of the synthesized compounds as AChEIs revealed that the 2-benzylamino derivative (7) showed twice the inhibitory activity of tacrine. Other 2-alkylamino compounds showed cholinesterase inhibitory activities comparable to or slightly higher than tacrine. However, results revealed that incorporation of an amide bond in the side chain at the 2-position is not preferable except if it is a part of a urea or thiourea side chains. Fusion of the pyridine ring to a pyrimidine nucleus was regarded in most cases unsuccessful in producing promising AChEIs. The in vivo screening of the synthesized compounds as AChEIs revealed that all compounds showed inhibitory effect equivalent to or significantly higher (2.5 fold) than tacrine with compounds 3b, 5 and 9 showing the highest in vivo percentage inhibition (>20% AChE inhibition compared to 9% in case of tacrine). It could be concluded that hydrolysis of the amide bondage and opening of the fused pyrimidine ring takes place during metabolism in vivo resulting in retaining the abolished activity of some products (3b and 5). In addition, hepatotoxicity screening of the compounds was estimated by determination of levels of SGPT and reduced GSH. SGPT testing indicated that all compounds were safe to the liver with ten compounds possessing hepatoprotective effect against the toxic effect of the solvent used (DMF). Furthermore, four compounds; 2, 3b, 4a and 4b were able to completely reverse the effect of the solvent and result in SGPT values almost similar to that of saline. Finally, the four most promising compounds that brought SGPT values back to normal were further investigated through determination of reduced GSH levels in rat liver after administration of the tested compounds. The results indicated that these compounds showed no hepatic injury and less GSH depletion than tacrine. Therefore, the hypothesis that the presence of a chloro group in tacrine related analogs results in encouraging anti-cholinesterase activity and most importantly reduced hepatotoxicity deserves further investigation. Furthermore, in silico physicochemical properties and pharmacokinetic parameters for the synthesized compounds were calculated using computer software and their practical logP determined. In addition, their drug-likeness score was calculated. Results indicated that all drugs are promising drug-like candidates. Finally, docking simulation of the in vitro most active compound 7 indicated superior binding to the receptor over tacrine.
    Experimental
    Funding
    Introduction Cholinesterases (ChEs) are a group of enzymes responsible for the hydrolysis of carboxylic and choline esters. These enzymes are diverse in their structure, function, location in body tissues, activity, and sensitivity towards a series of chemicals (Small et al., 1996). Besides their physiological role, distinct cholinesterasic isoenzymes present specific characteristics, namely in terms of affinity towards substrates and inhibition by environmental contaminants (Pope and Brimijoin, 2018). These enzymes are highly evolutionarily conserved, being present in several tissues of the most diverse organisms, invertebrates and vertebrates, in aquatic and terrestrial animals (Parmar et al., 1961, Sanchez-Hernandez and Sanchez, 2002, Cunha et al., 2007, Gagnaire et al., 2008, Santos et al., 2012, Alves et al., 2015). In fish, studies have demonstrated most frequently the presence of acetylcholinesterase (AChE) form as the predominant isoenzyme among all cholinesterases; this form is mainly located in the membrane of post-synaptic nervous cells, being involved in the control of neurotransmission through the hydrolysis of the neurotransmitter acetylcholine, a substrate by which it shows higher affinity. However, AChE also acts in the process of neuronal differentiation. Butyrylcholinesterase (BChE) is another common cholinesterase form found in fish, and can be found mainly in blood plasma. Its function is still little elucidated, but it seems to be involved in cell proliferation (Monteiro et al., 2005, Leticia and Gerardo, 2008, Nunes, 2011). Another isoenzyme that can be found in most organisms is propionylcholinesterase, a pseudocholinesterase with more affinity towards the substrate propionylcholine (Arufe et al., 2007, Nunes, 2011).