قاعدہ استصحاب کی حجیت پر اہل سنت اور اہل تشیع کی آرا ء کا تحقیقی و تقابلی مطالعہ

This research article is a comparative study of arguments on Istishab from Ahli-eSunnah and Ahli-e-Tashyyo School of thoughts. Istishab means presumption of continuity. The word "Istishab" also means the continuance of companionship. Technically it means the presumption of constant of an earlier rule or it continued absence. In this sense it means the maintenance of status with respect to the rule. The previous rule is accepted. Unless a new rule is found that goes against. It is an easy reference one may refer to "Istishab-ul-hal" as the "accompanying rule". But the fact is that, Istishab-ul-hal is not a source for establishing new rules, but it is merely a set of presumptions. Istishab has vital importance in Islamic jurisprudence. But the authenticity and Significance of "Istishab" only can prove through arguments therefore decided to arrange a unique and comparative study of ‘Istihab” form Ahil sunnat and Ahil tashyy School of thoughts. So we can prove the rule of Istishab as an authentic and acceptable rule for all Muslim.

Synthesis and Biological Activity of Quinazolines and Their Derivatives

Various chemists have attempted synthesis of a variety of quinazoline/quinazolinone compounds of versatile biological potential as they possess anticonvulsant and hypnotic, anticancer, antimicrobial and antihistaminic, diuretic, antimalarial, antihypertensive, antagonism of ghrelin receptor, antiinflammatory, analgesic and COX-2 inhibitory as well as antifungal activities. But, most of these studies were focused on the synthesis of 2-monosubstituted ones. Very few examples for the synthesis of 2,2-disubstituted quinazoline moieties have been recorded in literature but low yields, drastic reaction conditions and prolonged reaction times along with having lack of detailed biological activities study are the major drawbacks. Keeping in view, the biological importance of quinazoline/quinazolinone compounds, present work was designed to synthesize 2,2-disubstituted-2,3- dihydroquinazolin-4(1H)-ones 3a-h which possess quinazoline moiety, by exploring a facile and efficient synthetic methodology with excellent yield of the product (98.2 - 99.5%) and to study their biological activities. Nitro 4a-h, bromo 5a-h and N-alkylated / benzylated 6a-af derivatives of the 2,2-disubstituted-2,3- dihydroquinazolin-4(1H)-ones 3a-h were also synthesized. All synthesized compounds were biologically evaluated as inhibitors of cholinesterase and urease enzymes. Molecular docking study of the synthesized compounds was also conducted to optimize the in vitro results. GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1 was used to optimize the binding modes of the synthesized compounds. The computed binding modes in the active site of AChE and BChE are helpful in providing an insight into the enzyme inhibition mechanism. Computational predictions on the basis of ADMET SAR study was also carried out to get insight into pharmacokinetic properties of synthesized compounds in comparison to standard drug donepezil. Furthermore, computational studies like FMO and NBO analyses at the density functional theory (DFT) level using B3LYP/6-31G (d, p) method was carried out by employing Gaussian 09 software. Anti-cholinesterase assay results revealed that all the tested compounds showed activity against both AChE and BChE enzymes in micromolar to nanomolar range. Many compounds have shown the inhibition of both these enzymes higher than or comparable to the standard drug galatamine but few have displayed better activity even than donepezil. In general, some compounds having 4-chlorophenyl and di-isobutyl groups at C-2 position of quinazoline ring including 2-(4- chlorophenyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-one (3f), 2-(4-chloro-3- nitro-phenyl)-2-methyl-6,8-dinitro-2,3-dihydro-1H-quinazolin-4-one (4f), 6,8- dibromo-2-(3-bromo-4-chloro-phenyl)-2-methyl-2,3-dihydro-1H-quinazolin-4- one (5f), 1-(4-chloro-benzyl)-2-(4-chloro-phenyl)-2-methyl-2,3-dihydro-1Hquinazolin- 4-one (6x), 2,2-bis(2-methylpropyl)-2,3-dihydroquinazolin-4(1H)-one (3h), 6,8-dinitro-2,2-bis(2-methylpropyl)-2,3-dihydroquinazolin-4(1H)-one (4h), 6,8-dibromo-2,2-bis(2-methylpropyl)-2,3-dihydroquinazolin-4(1H)-one (5h), 1- benzyl-2,2-diisobutyl-2,3-dihydro-1H-quinazolin-4-one (6ad) and 1-(4-chlorobenzyl)- 2,2-diisobutyl-2,3-dihydro-1H-quinazolin-4-one (6af) possessed high AChE/BChE inhibitory activity in their respective series of analogues. Amongst all synthesized quinazoline moieties, compound 5f (selectivity index of 2.3 for AChE) with IC50value of 1.6±0.10 μM and 3.7±0.18 μM for AChE and BChE respectively and compound 6af (selectivity index of 2.6) with IC50 value of 0.6±0.01 (AChE) and 1.56 ±0.08 (BChE) can be considered as the most potent AChE/BChE dual inhibitors. Antiurease assay results revealed that compounds, 6,8-dinitro-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-one (4a), 6,8-dinitro-2,2- bis(2-methylpropyl)-2,3-dihydroquinazolin-4(1H)-one (4h), 1-benzyl-2-ethyl-2- methyl-2,3-dihydro-1H-quinazolin-4-one (6j), 1-(4-chloro-benzyl)-2,2-diethyl- 2,3-dihydro-1H-quinazolin-4-one (6p), 1-(4-chloro-benzyl)-2-methyl-2-propyl- 2,3-dihydro-1H-quinazolin-4-one (6t), 1-benzyl-2-isobutyl-2-methyl-2,3-dihydro- 1H-quinazolin-4-one (6z), 1-(4-chloro-benzyl)-2-isobutyl-2-methyl-2,3-dihydro- 1H-quinazolin-4-one (6ab) have good urease inhibitory potential. Amongst all tested moieties, compound, 2-methyl-6,8-dinitro-2-(3-nitro-phenyl)-2,3- dihydroquinazolin-4(1H)-one (4b) with IC50=8.70±0.19 μM and 1-(4-chlorobenzyl)- 2-ethyl-2-methyl-2,3-dihydro-1H-quinazolin-4-one (6l) with IC50= 6.55±0.15μM can be considered the strongest JBU inhibitor as compared to standard drug thiourea (21.0±0.01μM). Molecular docking study of the synthesized quinazoline/quinazolinone compounds against AChE and BChE revealed that dibromo derivatives 5a-h displayed better interaction with enzyme gorge than their dinitro 4a-h and unsubstituted 3a-h counterparts. But overall, N-substituted derivatives 6a-af displayed much better interactions among all synthesized quinazoline/quinazolinone compounds. Computational predictions on the basis of ADMET studies revealed that all the compounds except 4a-h have good pharmacokinetic properties as they are predicted to be absorbed in human intestine and also have the ability to cross blood brain barrier along with having no AMES toxicity and carcinogenicity. Non-carcinogenic and non-AMES toxicity of N-substituted compounds 6a-af is better than un-substituted quinazoline/quinazolinone compounds. The geometric parameters including bond length, bond angles and dihedral angles of compound 3a were optimized at B3LYP/6-31G (d, p) level of DFT. Calculated energy of HOMO and LUMO was -0.20651 eV and -0.02966 eV respectively. Whereas, selective Mullikan charges, ranged from -0.587 to 0.587 and NBO charge distribution varied from -0.711 to 0.711 on the heterocyclic ring of quinazoline core.