Abstract
Inhibiting the formation of amyloid fibrils is a crucial step in the prevention of the human neurological disorder, Alzheimer's disease (AD). Ionic liquid (IL) mediated interactions are an expedient approach that exhibits inhibition effects on amyloid fibrils. In view of the beneficial role of ILs, in this work we have explored complexation of anti-Alzheimer's drugs (i.e., tacrine and PC-37) and an amino acid-functionalized IL [AIL (4-PyC8)]. Maintaining standard physiological conditions, the binding mechanism, thermo-dynamical properties and binding parameters were studied by employing UV-vis, fluorescence, FTIR, 1H NMR, COSY and NOESY spectroscopy. The present investigation uncovers the fact that the interaction of anti-Alzheimer's drugs with 4-PyC8 is mediated through H-bonding and van der Waals forces. The Benesi–Hildebrand relation was used to evaluate the binding affinity and PC-37 showed the highest binding when complexed with 4-PyC8. FTIR spectra showed absorption bands at 3527.98 cm−1 and 3527.09 cm−1 for the PC-37 + 4-PyC8 system which is quite promising compared to tacrine. 1H-NMR experiments recorded deshielding for tacrine at relatively higher concentrations than PC-37. COSY investigations suggest that anti-Alzheimer's drugs after complexation with 4-PyC8 show a 1 : 1 ratio. The cross-peaks of the NOESY spectra involve correlations between anti-Alzheimer's drugs and AIL protons, indicating complexation between them. The observed results indicate that these complexes are expected to have a possible therapeutic role in reducing/inhibiting amyloid fibrils when incorporated into drug formulations.
Highlights
In the last few decades, targeted drug delivery has become a crucial issue in the bio-medical eld as it provides the undeniable advantage of minimizing the associated a er-effects of Paper50%).[10,11] It has been shown in the literature that amino acids can inhibit/arrest the polymerization of amyloid brils, which are responsible for causing neurological disorders.[12,13] Zaric et al has critically reviewed the role of various aromatic amino acids and their approach towards the inhibition of amyloid formation.[14]
Considering the imminent features of AILs and the requirement of potent anti-Alzheimer's drugs, we have investigated the binding interaction of anti-Alzheimer's drugs, namely tacrine and PC-37 with AIL i.e., 4-((hydroxyimino) methyl)-1-(2-(octylamino)-2-oxoethyl)pyridin-1-ium bromide (4PyC8) at 310 K and 7.5 pH
The absorption spectra of tacrine and PC-37 in aqueous solutions with increasing concentrations of 4-PyC8 are shown in Fig. S1.† The increasing spectral intensities indicate the interaction between the antiAlzheimer's drugs and AIL (4-PyC8) and the formation of a new complex
Summary
In the last few decades, targeted drug delivery has become a crucial issue in the bio-medical eld as it provides the undeniable advantage of minimizing the associated a er-effects of Paper50%).[10,11] It has been shown in the literature that amino acids can inhibit/arrest the polymerization of amyloid brils, which are responsible for causing neurological disorders.[12,13] Zaric et al has critically reviewed the role of various aromatic amino acids and their approach towards the inhibition of amyloid formation.[14]. Alzheimer's disease (AD) is a neurological disorder which signi cantly imbalances the socio-economy of the world.[17] AD is broadly de ned as memory loss, leading to a continuous decline in thinking capacity that disrupts a person's ability to function independently.[18] Despite a long history of intensive research, AD still lacks efficient medical counter measures and potent anti-Alzheimer's drugs.[19] a few anti-Alzheimer drugs have been approved by the US Food and Drug Administration (FDA), but those are helpful only for short-term symptomatic relief and are accompanied by various side-effects.[20,21] Tacrine (1,2,3,4-tetrahydroacridin-9amine) was the rst drug approved by the FDA in 1993; it is a reversible AChE inhibitor that interacts with the a-anionic site of the enzyme It was discontinued in 2013 due to its hepatotoxicity.[22] Despite this, the tricyclic structure of tacrine is still preferred for the design of new anti-Alzheimer's drug candidates serving as a template inhibitor.[23,24] Likewise, PC-37 (7-methoxy-N-(2-{4-[(3-methylphenyl)methyl]piperazin-1-yl} ethyl)-1,2,3,4-tetrahydroacridin-9-amine trihydrochloride) is a cholinesterase inhibitor conjugating 7-methoxytacrine and donepezil templates into one chemical entity.[25] The bioavailability expressed as AUCtotal was 28 179 Æ 4691 min ng mLÀ1 for PC-37 and it was found to be capable of targeting the central nervous system at elevated concentrations. It is expected that the complexes formed between the AIL and antiAlzheimer's drugs could be of bene t and will be revolutionary in the development of modi ed anti-Alzheimer's drugs
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