New Multitarget Hybrids Bearing Tacrine and Phenylbenzothiazole Motifs as Potential Drug Candidates for Alzheimer's Disease

• Published in: Molecules (Basel, Switzerland) Vol. 24; no. 3; p. 587
• Main Authors: Rajeshwari, Rajeshwari, Chand, Karam, Candeias, Emanuel, Cardoso, Sandra M, Chaves, Sílvia, Santos, M Amélia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 07.02.2019; MDPI
• Subjects: Acetylcholinesterase; acetylcholinesterase inhibitors; Alzheimer's disease; Amino acids; Amyloid; Aβ aggregation; benzothiazole; Crystal structure; Design; Drug development; Drugs; Enzymes; Hybrids; Lead compounds; Life expectancy; Life span; Ligands; multitarget; Neuroblastoma; Neuroblasts; Neuroprotection; Neurotoxicity; Oxidative stress; Pharmacokinetics; Pharmacophores; Simulation; Tacrine; tacrine hybrids; Toxicity; Aβ aggregation; acetylcholinesterase inhibitors; tacrine hybrids; Alzheimer’s disease; benzothiazole; multitarget
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24030587

Research on neurodegenerative brain disorders, namely the age-dependent Alzheimer's disease (AD), has been intensified in the last decade due to the absence of a cure and the recognized increasing of life expectancy for populations. To address the multifactorial nature and complexity of AD, a multi-target-directed ligand approach was herein employed, by designing a set of six selected hybrids ( ⁻ ) that combine in the same entity two pharmacophores: tacrine (TAC) and 2-phenylbenzothiazole (PhBTA). The compounds contain a methoxy substituent at the PhBTA moiety and have a variable length linker between that and the TAC moiety. The docking studies showed that all the compounds assure a dual-binding mode of acetylcholinesterase (AChE) inhibition, establishing π-stacking and H-bond interactions with aminoacid residues at both active binding sites of the enzyme (CAS and PAS). The bioassays revealed that the designed compounds display excellent AChE inhibitory activity in the sub-micromolar range (0.06⁻0.27 μM) and moderate inhibition values for amyloid-β (Aβ) self-aggregation (27⁻44.6%), compounds and being the lead compounds. Regarding neuroprotective effects in neuroblastoma cells, compounds , and revealed the capacity to prevent Aβ-induced toxicity, but compound showed the highest neuroprotective effect. Overall these hybrid compounds, in particular and , with promising multitarget anti-AD ability, encourage further pursuing studies on this type of TAC-PhBTA derivatives for potential AD therapy.