مولانا حبیب الرحمن خاں شروانی
افسوس ہے کہ گزشتہ مہینہ نواب صدریار جنگ مولانا حبیب الرحمن خاں صاحب شروانی نے۸۶سال کی عمر میں وفات پائی۔۱۸۵۷ء کے ہنگامے کے بعد جن اکابر علم وادب نے اس ملک میں مسلمانوں کی نشاۃ ثانیہ کاسروسامان کیا تھا مولاناان کے زمرہ میں ایک نوجوان رفیق کی حیثیت سے شامل تھے اس لیے انھوں نے اس دور کی بہار سامانیاں خوداپنی آنکھ سے دیکھی تھیں اور اپنی خداداد صلاحیت وقابلیت سے کام لے کر ان کی تعمیر وترقی میں خود بھی عملی حصہ لیا تھا۔ مسلم یوینورسٹی علی گڑھ، ندوۃ العلما، دارالمصنفین اعظم گڑھ، مسلم ایجوکیشنل کانفرنس، دارالعلوم دیوبند،حیدرآباد کامحکمہ امور مذہبی،یہ سب ادارے مرحوم کی اصلاحی و تدبیری کاوشوں اورگوناگوں ہمدردانہ دلچسپیوں کے جولانگاہ تھے۔دولت زرکی بہتات کے ساتھ دولت علم وفضل سے بھی مالا مال تھے۔ مرحوم کاکتب خانہ ہندوستان کاایک بہترین کتب خانہ تھا جہاں ریسرچ اسکالر آکر مطالعہ وتحقیق کی تشنگی بجھاتے تھے۔ کتابوں کی حفاظت ونگرانی اوران کی ترتیب وفہرست سازی کا خاص اہتمام کرتے تھے۔ ذوق مطالعہ کایہ عالم تھا کہ ضعف ونقاہت اوربیماری کے باوجود روزانہ پندرہ گھنٹے کتب خانہ میں پابندی کے ساتھ بیٹھتے اورمطالعہ کرتے تھے۔ متعدد کتابیں اوربہتیرے مقالات بھی ان کے قلم سے نکلے،اردو کے صاحب طرز ادیب تھے۔فارسی اورعربی شعروادب کاشگفتہ ذوق رکھتے تھے۔ دین داری اورمذہبی شعائر وآداب کااحترام ان کی فطرت تھی۔ اخلاق و عادات، طورواطوار کے لحاظ سے اب سے ڈھائی تین سو برس پہلے کی اسلامی تہذیب و شرافت کازندہ نمونہ تھے،خودداری کے ساتھ ملنساری،تمکنت کے ساتھ ارباب علم وادب کے ساتھ انکساری ان کی طبیعت کاجوہر تھا۔ انھوں نے اپنے علم وفضل سے بھی خلق خدا کوفیض پہنچایا اور دولت و ثروت سے بھی،ان چند درچند خصوصیات وکمالات کے جامع ہونے کے اعتبار سے مرحوم مسلمانوں کے اس دور میمون و مبارک کی یادگار تھے...
إعداد الباحث: بندر بن أحمد بن ثابت عاتي: قسم الكتاب والسنة، كلية الدعوة وأصول الدين، جامعة أم القرى، المملكة العربية السعودية
الملخص:
إن من جملة المناسك ما حدَّه النبي من المواقيت المكانية التي لا تجوز مجاوزتها بغير إحرام منها لمريد الحج أو العمرة، وإن المواقيت المكانية ذات أهمية كبيرة؛ ويقع الكثير من المسلمين في حرج وإشكال؛ لعدم فقههم بمسائل الحج والعمرة، فربما لا يتم حجه، وربما تجب عليهم الفدية، وهذا تحديداً ما يحاول الباحث قراءته بشكل تحليلي، ولذلك فقد قام الباحث بتحليل الأحاديث الواردة في المواقيت المكانية ، مع بيان المسائل الفقهية ودراستها دراسةً موضوعيةً، وخرجت الدراسة بعدة نتائج منها: وجوب الإحرام من المواقيت، ومن تركه عليه دم. وأنَّ المواقيت توقيفية لا تجوز مجاوزتها لمريد النسك. ومشروعية المحاذاة وأنها معتبرة. وأنَّ مدار الخلاف في مسألة هل جدة ميقات، هو بيان المقصود بالمحاذاة. أن جدة ليست ميقاتًا إلا لأهلها ومن حاذاها من الغرب. وأن المواقيت لأهلها ولمن مرَّ عليها من غير أهلها. جواز الإحرام من الطائرات والسفن بالمحاذاة.
الكلمات المفتاحية: أركان الإسلام، الحج، مناسك الحج، المواقيت المكانية
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.