Synthesis of potential dual binding site acetylcholinesterase inhibitors through an efficient solid phase approach based on the Mitsunobu reaction

Leonetti, Francesco; Cappa, Anna; Maccallini, Cristina; Carotti, Angelo

doi:10.3998/ark.5550190.0005.524

Cited by 9 publications

(6 citation statements)

References 7 publications

(5 reference statements)

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“…A solid phase synthesis of a number of monoamino and diamino derivatives as potential dual binding site AChE inhibitors was developed by Leonetti et al (Scheme 161). 1611 The first Mitsunobu reaction was efficiently carried out with Ph 3 P-DIAD in THF, whereas the two subsequent reactions, allowing the introduction of an aliphatic spacer linked to a second phenolic moiety and leading to 541, were more efficiently performed using n-Bu 3 P-ADDP in CH 2 Cl 2 . A high-loading soluble star-polymer based on a cyclophosphazene skeleton has been prepared by Reed and Janda.…”

Section: Polymer Supports In the Mitsunobu Reactionmentioning

confidence: 99%

Mitsunobu and Related Reactions: Advances and Applications

et al. 2009

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His research interests include Organophosphorus Chemistry and Main Group Chemistry. He has over 115 publications so far and is a fellow of the Indian Academy of Sciences, Bangalore. N. N. Bhuvan Kumar was born in Cherukupalli, Guntur, India. After completing his B.Sc. from Nagarjuna University, he joined the School of Chemistry, University of Hyderabad, as a postgraduate student in the year 2000 and obtained his Master's degree in Chemistry. Currently, he is pursuing a Ph.D. on Organophosphonates under the supervision of Prof. K. C. Kumara Swamy. E. Balaraman was born in Kancheepuram, Chennai, India, in 1980. He received his M.Sc. in Chemistry from Vivekananda College [Madras University (2002)] and his Ph.D. degree in the areas of organophosphonates and modified BINOLs under the guidance of Prof. K. C. Kumara Swamy. Presently he is a postdoctoral fellow with Professors David Milstein and Ronny Neumann at the Weizmann Institute of Science, Israel. K. V. P. Pavan Kumar was born in Hyderabad (Andhra Pradesh), India, in 1979. He obtained his B.Sc. (Chemistry Honors) and M.Sc. (Chemistry) degrees from Sri Sathya Sai Institute of Higher Learning, Puttaparthi, A.P., India. He obtained his Ph.D. degree under the guidance of Prof. K. C. Kumara Swamy in October 2006. Presently he is working as a postdoctoral fellow in the area of hydroamination reactions using new titanium catalysts with Prof. Pierre Le Gendre at the Universite ´de Bourgogne, France.

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Section: Polymer Supports In the Mitsunobu Reactionmentioning

confidence: 99%

Mitsunobu and Related Reactions: Advances and Applications

et al. 2009

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“…Molecular dynamics simulations were carried out for each molecule and molecular descriptors were determined followed by QSAR linear regression study (Table ). The correlation model showed a linear plot for both measured IC 50 values and values predicted for the training set of molecules (Figure ). ,,, The correlation analysis showed an RMSD of 4.0 and r 2 value of 0.86. This linearity for the model indicates the reliability of QSAR to compare and predict the activity of a test set molecules (Figure ).…”

Section: Resultsmentioning

confidence: 88%

“…As acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD. ,− Pyrimidine derivatives were therefore built and screened virtually using the docking method.…”

Section: Resultsmentioning

confidence: 99%

“…The correlation model showed a linear plot for both measured IC 50 values and values predicted for the training set of molecules (Figure 7). 23,38,58,61 The correlation analysis showed an RMSD of 4.0 and r 2 value of 0.86. This linearity for the model indicates the reliability of QSAR to compare and predict the activity of a test set molecules (Figure 8).…”

Section: Weinerpolmentioning

confidence: 97%

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Acetylcholinesterase Inhibitors: Structure Based Design, Synthesis, Pharmacophore Modeling, and Virtual Screening

Valasani

Chaney

Day

et al. 2013

J. Chem. Inf. Model.

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Acetylcholinesterase (AChE) is a main drug target, and its inhibitors have demonstrated functionality in the symptomatic treatment of Alzheimer's disease (AD). In this study, a series of novel AChE inhibitors were designed and their inhibitory activity was evaluated with 2D quantitative structure-activity relationship (QSAR) studies using a training set of 20 known compounds for which IC₅₀ values had previously been determined. The QSAR model was calculated based on seven unique descriptors. Model validation was determined by predicting IC₅₀ values for a test set of 20 independent compounds with measured IC₅₀ values. A correlation analysis was carried out comparing the statistics of the measured IC₅₀ values with predicted ones. These selectivity-determining descriptors were interpreted graphically in terms of principal component analyses (PCA). A 3D pharmacophore model was also created based on the activity of the training set. In addition, absorption, distribution, metabolism, and excretion (ADME) descriptors were also determined to evaluate their pharmacokinetic properties. Finally, molecular docking of these novel molecules into the AChE binding domain indicated that three molecules (6c, 7c, and 7h) should have significantly higher affinities and solvation energies than the known standard drug donepezil. The docking studies of 2H-thiazolo[3,2-a]pyrimidines (6a-6j) and 5H-thiazolo[3,2-a] pyrimidines (7a-7j) with human AChE have demonstrated that these ligands bind to the dual sites of the enzyme. Simple and ecofriendly syntheses and diastereomeric crystallizations of 2H-thiazolo [3,2-a]pyrimidines and 5H-thiazolo[3,2-a] pyrimidines are described. The solid-state structures for the HBr salts of compounds 6a, 6e, 7a, and 7i have been determined using single-crystal X-ray diffraction techniques, and X-ray powder patterns were measured for the bulk solid remaining after solvent was removed from solutions containing 6a and 7a. These studies provide valuable insight for designing more potent and selective inhibitors for the treatment of AD.

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“…The 1,4-dialkoxybutane moiety is widely found in many natural products 1 and bioactive molecules, 2 such as the C-analogue of a blood group antigen (H-antigen) and acetylcholinesterase (AChE) inhibitors (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%