Design, Synthesis, and Pharmacological Evaluation of Novel Tacrine Derivatives as Multi-target ANTI-Alzheimer's Agents In Rat Models.

BACKGROUND: Alzheimer's disease is a progressive neurodegenerative disorder for which no curative drugs are available and treatment available is just palliative. OBJECTIVES: Current research focused on design of Tacrine-Flavone hybrids as multitargeted cholinesterase and monoamine oxidase B inhibitors. METHODS: A total of 10 Tacrine- Flavone hybrids were designed, synthesized and characterized. The in vitro neurotoxicity and hepatotoxicity of the synthesized compounds determined using SHSY5Y cell line and HEPG2 cell line. One most active compound (AF1) with least toxicity in in vitro studies was chosen for in vivo studies. Acute and subacute toxicity of the novel compound AF1 conducted on Wistar rats according to OECD guideline 423 and 407. The LD50 value of the novel compound calculated according to Finney's method using Probit analysis. Anti-Alzheimer's activity studies conducted on male Wistar rats. Behavioral studies conducted and AChE and MAO-B activity determined in rat brain. RESULTS AND DISCUSSION: All the compounds exhibited good inhibitory effect on MAO B and AChE. The neurotoxicity studies of the active compound AF1 did not show toxicity up to 100µg. The hepatotoxicity study of the most active compound AF1, showed the compound to be safe up to 200µg. The LD 50 value of the novel compound after a single oral administration was found to be 64 mg/kg bodyweight in rats. Subacute toxicity studies did not show any remarkable toxicity in the vital organs up to 40 mg/kg. Activity studies showed comparable results with standard at 20 mg/kg. CONCLUSION: The results showed that the novel Tacrine-Flavone hybrids are multitarget-directed ligands, which are safe and active compared to tacrine and can be a promising lead molecule for further study.

Design Synthesis and in vitro Evaluation of Tacrine-flavone Hybrids as Multifunctional Cholinesterase Inhibitors for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. The multifactorial etiology of AD has led to the design of multitarget directed ligands (MTDL) for AD. Tacrine an acetylcholinesterase (AChE) inhibitor was the first FDA approved drug for AD but is discontinued due to hepatotoxicity. OBJECTIVE: Present research focused on incorporating a flavone to the tacrine nucleus to enhance the anti-Alzheimer's property of the tacrine with the synergistic effect of flavone which is a very good antioxidant. It is expected that the antioxidant property and hepatoprotective nature of flavones will reduce the hepatotoxic side effect of tacrine. METHODS: We designed and synthesized ten flavone substituted tacrine derivatives and evaluated for in vitro AChE and BuChE inhibitoy activity by modified Ellman's method using eeAChE and eqBuChE. In vitro antioxidant activity was studied by DPPH radical scavenging assay. Molecular modeling studies were conducted in Schrodinger and AutoDock Vina with TcAChE(PDB ID:1H23),hAChE(PDB ID:4EY7) and hBuChE(PDB ID:4TPK). RESULTS: All the compounds exhibited potent inhibitory effect on AChE and BuChE with IC50 values in µM concentration. The compounds exhibited very good antioxidant activity in DPPH radical scavenging assay. Among the compounds the compound AF1 showed highest activity with IC50 value of 0.93 µM for AChE and 1.48 µM for BuChE and also showed significant antioxidant activity (2.6 nM). A correlation graph was plotted for IC 50 values vs Dock score and the results are promising with r2 values of 0.62 and 0.73 for AChE and BuChE inhibition respectively which proved the reliability of docking approaches. CONCLUSION: The results highlighted the multifunctional nature of the novel Tacrine-Flavone hybrids and they may be promising MTDL for AD.

Impact of land cover and land use change on runoff characteristics.

Change in Land Cover and Land Use (LCLU) influences the runoff characteristics of a drainage basin to a large extent, which in turn, affects the surface and groundwater availability of the area, and hence leads to further change in LCLU. This forms a vicious circle. Hence it becomes essential to assess the effect of change in LCLU on the runoff characteristics of a region in general and of small watershed levels (sub-basin levels) in particular. Such an analysis can effectively be carried out by using watershed simulation models with integrated GIS frame work. SWAT (Soil and Water Analysis Tool) model, being one of the versatile watershed simulation models, is found to be suitable for this purpose as many GIS integration modules are available for this model (e.g. ArcSWAT, MWSWAT). Watershed simulation using SWAT requires the land use and land cover data, soil data and many other features. With the availability of repository of satellite imageries, both from Indian and foreign sources, it becomes possible to use the concurrent local land use and land cover data, thereby enabling more accurate modelling of small watersheds. Such availability will also enable us to assess the effect of LCLU on runoff characteristics and their reverse impact. The current study assesses the effect of land use and land cover on the runoff characteristics of two watersheds in Kerala, India. It also assesses how the change in land use and land cover in the last few decades affected the runoff characteristics of these watersheds. It is seen that the reduction in the forest area amounts to 60% and 32% in the analysed watersheds. However, the changes in the surface runoff for these watersheds are not comparable with the changes in the forest area but are within 20%. Similarly the maximum (peak) value of runoff has increased by an amount of 15% only. The lesser (aforementioned) effect than expected might be due to the fact that forest has been converted to agricultural purpose with major portion as plantations which have comparatively similar characteristics of the forest except for evapo-transpiration. The double sided action (increase in evapo-transpiration owing to species like rubber and increase percolation due to its plantation method by using terracing) might be the reason for relatively smaller effect of the land use change, not commensurate with the changes in the forest area amounting to 60% and 32% for Manali and Kurumali watersheds respectively. Water harvesting methods like rain harvesting ditches can be made mandatory where species with high evapo-transpiration are grown. This action shall enhance the groundwater percolation and shall counter act the effect due to high evapo-transpiration.