ظہرین کے اوقات میں اشتراکات: اسلام کے پانچ بڑے فقہی مکاتب فکر کے تناظر میں

In India scholar‘s had played incredible role for ‘Hadith’. The service of Indian Muslim scholars about methodology of Hadith is much more than other countries scholars in the last 50 years of thirteenth century. Their name should be written in golden words. There services about the methodology of Hadith are great one. Muslim scholars of sub-continent had taken keen interest in the research work of Hadith and its explanation. If we evaluate the theological history of India that ; Shah Waiullah ‘and his family worked day and night for expansion and publishing of’ Hadith  ‘ Thirteenth century of hire is called a century of revolution as concerned for Hadith. Because in that era proper theological institutions were set up and very strong institutions had spread knowledge and study of methodology of Hadith

9-Aminacridine Derivatives As Potential Antialzheimer Agents: Insilico Analysis, Synthesis and Biological Evaluation

Alzheimer''s disease (AD) is a multifactorial neurodegenerative disorder mainly characterized by progressive deterioration of memory and impaired cognitive function. It is the leading cause of dementia, responsible for about half of all cases worldwide. Cholinergic enzyme deficiency, oxidative stress, formation of amyloid beta (Aβ) plaques and neurofibrillary tangles are known main factors involved in the pathogenesis of AD. The most promising approach for symptomatic relief of AD is to inhibit acetylcholinesterase (AChE), which primarily catalyzes the hydrolysis of acetylcholine (ACh), thereby increasing synaptic levels of ACh in the brain. Crystal structures revealed that it has a peripheral anionic site (PAS) located at the mouth of the narrow gorge entry lined with multiple conserved amino acid residues and catalytic active site (CAS) having choline binding site, an acyl pocket, oxyanion hole and esteratic subunit (catalytic triad). It is also found that AChE present in the cholinergic terminals accelerates Aβ plaque aggregation. Tacrine (1,2,3,4-tetrahydro-9-aminoacridine) the first approved drug as an AChE inhibitor for the treatment of AD is a derivative of 9-aminacridine (9AA). In the present research work a comparative molecular docking approach using MOE and Autodock was taken to identify the potential 9AA analogues as AChE inhibitors. Moreover to test these molecules for having ability to reduce the oxidative stress as well as inhibition of fibril aggregation. In-house library containing forty six proposed 9AA derivatives was docked against human acetylcholinesterase (hAChE) (PDB ID: 4EY7), retrieved from virtual protein databank (PDB). The docking protocol as validated by reproduction of binding pose of the co-crystallized ligand donepezil in the enzyme active site. To further substantiate the protocol, some reported AChE inhibitors like tacrine, physostigmine, rivastigmine and galantamine were also docked within the active site. In addition, drug-likeness score responsible for a good pharmacokinetic property was also calculated. All the compounds followed Lipinski’s rule of five, making them potentially promising drug candidates for the treatment of Alzheimer’s disease. Top Ten molecules were selected for synthesis and biological investigation based on best docking energy and conformations in which compounds were bound to PAS and CAS regions of AChE through hydrogen bonding, π-π, π-CH and hydrophobic interactions. All compounds were accommodated in the active site by blocking the entrance of gorge area (PAS) and extending to CAS region mostly touching choline and acyl binding regions of AChE. Most common active site residues displayed by both soft wares were Asp74, Trp86, Tyr124, Trp286, Phe295, Phe297, Tyr133, Tyr337, Phe338 and Tyr341. Molecules were synthesized by targeting the 9-amino group of aminoacridine with substituted and unsubstituted benzoyl, phenacyl, sulphonyl and naphthoyl halides. Physical, chromatographic and spectroscopic techniques were used to confirm the synthesis and structure elucidation of molecules. Designed molecules comprised three main structural features first acridine ring with primary amine, second central sulphonyl, acyl and carbonyl moieties linking acridine amine and aromatic ring system and third, terminal substituted/unsubstituted single or fused aromatic ring system. These features makes the molecules somewhat similar to endogenous substrate ACh and enhancing affinity and binding with target active site. Invitro AChE inhibition was investigated by Ellman’s method. All derivatives effectively inhibited AChE with potencies in the micromolar ranges (IC50 0.261- 26.183µM). Outcomes of the enzyme inhibition study justified the molecular docking results. Promising enzyme blocking potential of all compounds specially PS23, PS25 and PS28 signified the importance of the connecting moiety and substitution on phenyl ring and suggesting their incorporation in the therapeutic activity. Sulphonyl and carbonyl oxygen presenting opportunity for hydrogen bonding along with acridine amines while aromatic ring substituted with lipophilic group (para position) along with the acridine ring system helping the molecules to fit in the active area with the help of π-π and hydrophobic interactions. These features providing not only the best affinity for target enzyme but also stabilized the complex more efficiently. Antioxidant activity through DPPH scavenging ability showed pronounced results with IC50 values ranging from 0.0294 to 0.811µM. Although all ligands demonstrated better results than parent and standard but PS25 and PS28 are supposed to be best candidates because of their optimal antioxidant property. Potential of the molecules to inhibit the fibril aggregation was also investigated and all compounds were unable to stop the fibril formation process at tested doses. Cytotoxicity screening of all derivatives were performed by using 3T3 cell line. All compounds showed better safety profile as compared to reference cytotoxic drug in terms of higher IC50 values. PS24, PS32 and PS33 displayed best results among all derivatives, PS25 and PS28 also exhibited good results. Amongst all synthesized tested ligands PS23, PS25 and PS28 appeared as most promising multitargeted candidates. The molecular modeling studies indicated that our synthetic derivatives have significant binding affinity with both CAS and PAS of the AChE. They exhibited profound AChE inhibition as main therapeutic target and endowed with advantageous antioxidant power as additional supportive therapy which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit. Over all this study suggest that compounds PS23, PS25 and PS28 offer an attractive starting point for further lead optimization in the drug discovery process against AD.