Design, synthesis and neuroprotective evaluation of novel tacrine–benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease

Keri, Rangappa S.; Quintanova, Catarina; Marques, Sérgio M.; Esteves, A. Raquel; Cardoso, Sandra M.; Santos, M. Amélia

doi:10.1016/j.bmc.2013.05.028

Cited by 90 publications

(48 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(171) has shown good LPI and EHI along with moderate SASA and 6-methoxy-benzothiazole-2-amine(172) displayed excellent IL-1b inhibitory activity with IC 50 values between 6.83 and 7.66 mM with respect to piroxicam (21.33 mM) as standard. Compounds having methoxy or nitro substituent, on BTA core have exhibited very good antiinflammatory activity while showing good antioxidant potential [203].…”

mentioning

confidence: 95%

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Keri

Patil

et al. 2015

European Journal of Medicinal Chemistry

Self Cite

456

238

View full text Add to dashboard Cite

mentioning

confidence: 95%

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Keri

Patil

et al. 2015

European Journal of Medicinal Chemistry

Self Cite

456

238

View full text Add to dashboard Cite

“…14,22 Furthermore this new set of eight hybrids was designed by selection of suitable linkers to enable a dual mode binding, via the tacrine and BTA moieties, with both active binding sites of AChE. Besides the description of the design and synthetic procedures, we include herein the results and discussion of the bioassays, namely the inhibition of AChE, Af3 aggregation, MAOs and anti-oxidant properties, as well as their effect on the neuronal cell viability upon being subjected to model stressors of AD.…”

Section: Insert Here Figmentioning

confidence: 99%

“…14,15,16 Very recently, the conjugation of tacrine (TAC) with S-allylcysteine (SAC) and S-propargylcysteine (SPRC), two natural based products with neuroprotective and antioxidant roles (e.g. garlic derivatives), 17,18 resulted in a set of bihybrids (TAC-SAC and TAC-SPRC) with important neuroprotecting properties which, besides the expected AChEI and anti-oxidant properties, presented also inhibitory activity for the self-and Cuinduced Af3 aggregation.…”

Section: Introductionmentioning

confidence: 99%

Tacrine-allyl/propargylcysteine–benzothiazole trihybrids as potential anti-Alzheimer's drug candidates

et al. 2016

Self Cite

View full text Add to dashboard Cite

On continuing our research on new drug candidates for Alzheimer´s disease (AD), we have designed, synthesized and evaluated a series of multifunctional trihybrid agents.The design strategy was based on the incorporation of a benzothiazole (BTA) moiety on a series of very recently reported bihybrids, resulting from the conjugation of a tacrine (TAC) with natural based moieties, namely S-allylcysteine (SAC) (garlic constituent) and S-propargylcysteine (SPRC). Thus, in addition to the acetylcholinesterase inhibition (AChEI) and anti-ROS capacity of the bihybrids (TAC-SAC/SPRC), the new trihybrids (TAC-SAC/SPRC-BTA) appeared endowed with 5-fold capacity for inhibition of the amyloid beta-peptide (Af3) aggregation. The BTA moiety led also to considerable enhancement of the AChEI on the trihybrids, which molecular modeling suggested as being due to the simultaneous binding to the catalytic active site and peripheral anionic site of AChE. The trihybrids were also assessed for the MAO inhibition, but resulted in lower activity than expected, ascribed to the low accessibility of the propargyl groups to the enzyme active site. Finally, the effects of the compounds on the viability of neuroblastome cells stressed with Af342 and H2O2 showed moderate cell protection. Overall, the performed studies illustrate the importance (and limitations) of enclosing several molecular scaffolds in one molecular entity to allow the modulation of multiple AD targets.

show abstract

“…This same approach has been applied to the discovery or development of compounds that could target several diseases [17,18]. One of the strategies at the forefront of drug discovery is the virtual screening of databases [19], which can identify powerful new protein ligands [20,21].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

Cabarcas-Montalvo

Maldonado-Rojas

Montes-Grajales

et al. 2016

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

Background: Dengue disease is a global disease that has no effective treatment. The dengue virus (DENV) NS2B/NS3 protease complex is a target for designing specific antivirals due to its importance in viral replication and its high degree of conservation.Methods: NS2B/NS3 protease complex structural information was employed to find small molecules that are capable of inhibiting the activity of the enzyme complex. This inhibitory activity was probed with in vitro assays using a fluorescent substrate and the complex NS2B/NS3 obtained by recombinant DNA techniques, for testing the activity against dengue virus replication, HepG2 cells infected with dengue virus serotype 2 were used. Results: A total of 210,903 small molecules from PubChem were docked in silico to the NS2B/NS3 structure (PDB: 2FOM) to find molecules that were capable of inhibiting this protein complex. Five of the best 500 leading compounds, according to their affinity values (-11.6 and -13.5 kcal/mol), were purchased. The inhibitory protease activity on the recombinant protein and antiviral assays was tested. Conclusions: Chemicals CID54681617, CID54692801 and CID54715399 were strong inhibitors of NS2B/NS3, with IC 50 values (µM) and percentages of viral titer reductions of 19.9, 79.9%; 17.5, 69.8%; and 9.1, 73.9 %, respectively. Multivariate methods applied to the molecular descriptors showed two compounds that were structurally different from other DENV inhibitors. General significance: This discovery opens new possibilities for obtaining drug candidates against Dengue virus.

show abstract

Design, synthesis and neuroprotective evaluation of novel tacrine–benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease

Cited by 90 publications

References 51 publications

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Tacrine-allyl/propargylcysteine–benzothiazole trihybrids as potential anti-Alzheimer's drug candidates

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

Contact Info

Product

Resources

About