سد الذرائع حقيقته ونماذج من تطبيقاته المعاصرة

Today’s world is a global village. Societies affect each other far deeper and faster than ever. New problems are sprouting with every coming day. We feel that the cultural issues are the most significant ones in this context. The question is how we should deal with these problems. To us, the solution lies in the concept of Sadd al-Dharā’i‘(prevention), one of the instruments of Sharī‘ah (Islamic Law). Such is its importance as all the four schools of thought are of the same opinion about its scope. A cultural change if drives Muslims away from the objectives of Sharī‘ah, it will have to be stopped or altered to suit the objectives, but if it leads to something good without damaging the objectives of Sharī‘ah, it will be accepted. New problems are multifarious. We need to bring ijtihād into practice and solve such problems. This research article discusses the concept of Sadd al-Dharā’i‘(prevention.), its meaning, definition, and scope. It also discusses different opinions of scholars. The author of this paper, then, deliberates its use for its applications to solve the new problems being faced by the Muslims across the world.

Synthesis, Identification, Biological Investigation and Molecular Docking Studies of Aromatic/Heterocyclic Derivatives As Monoamine Oxidase Inhibitors

Monoamine oxidase inhibition offers potential therapeutic target for the management of depression and Parkinson’s disease. Keeping this in view, the present study was designed to select and synthesize potential scaffolds followed by monoamine oxidase inhibition, computational studies, behavioral and neurochemical assessments. Five different types of scaffolds (pyrazolobenzothiazine-based carbothioamides, chromones, chalcones and quinoline carboxylic acid derivatives) and a synthetic compound oxatomide were selected for this study based on their potential to interact therapeutically with MAO enzyme. Their various derivatives were synthesized and structurally characterized using spectroscopic methods i.e., mass and NMR. All compounds were subjected to monoamine oxidase A and B inhibition assay using the kynuramine or the amplex red method. The data showed that pyrazolobenzothiazinebased carbothioamides held significant potential to inhibit both MAO-A and B. Compounds 2-(4-(3,4-dimethyl-5,5-dioxidobenzo pyrazolo[4,3-c][1,2]thiazin-2(4H)yl) benzylidene)-N-(p-tolyl) hydrazine carbothioamide (3b) (IC50 = 0.003 ± 0.0007 mM) and N-(4-ethylphenyl)-2-(4-(4-methyl-5,5-dioxido-3-phenylbenzo pyrazolo[4,3c][1,2]thiazin-2(4H)-yl) benzylidene) hydrazine carbothioamide (4d) (IC50 = 0.02 ± 0.001 mM) inhibited the enzyme with efficacy comparable to that of the standard inhibitors, clorgyline and deprenyl. Computational docking studies revealed that 3b showed interaction to Tyr407 and Tyr444 pi-interactions from 4-methylphemyl zone of molecule, and the bezothiazine ring was oriented to hydrophobic pocket of the active site. The amino acids Ile325, Ile335, Phe352, Tyr69 and Tyr197 showed Van der Waals interactions while amino acids Tyr407, Gln215, Val210, Phe208, Ile180, and Cys323 showed polar interaction to flavin adenine dinucleotide (FAD). Kinetic data revealed compound 3b as a noncompetitive inhibitor. Phenothazine ring of 4d showed pi-stacked-interactions to Tyr398 and Tyr435. Ethylphenyl-side was oriented to entrance cavity. Van der Waals interactions were found with Phe103, Leu164, Phe168, Ile199, Tyr326 and Phe34. Apart from π-π interactions with the Tyr398 and Tyr435, FAD and other residues such as Gln206 and Ile316 showed polar interactions with 4d. Thus aryl substitution was necessary for the observed function of these molecules. Enzyme kinetics showed 4d to be a competitive inhibitor for MAO-B. These compounds were tested for their efficacy in-vivo. The compound 3b caused significant decline in the immobility time in tail suspension test, while compound 4d significantly reversed the effect of rotenone as suggested by the remarkable increase in time spent on Rotarod. Hence, it can be deduced that both of this compounds have the ability to reach CNS to produce their desired effects. Their effects were further confirmed by neurotransmitter analysis. The brains from 3b treated animals showed significant increase in the levels of norepinephrine and serotonin alone with decline of its metabolite i.e., 5-hydroxyindoleacetic acid. However, the 4d treatment caused significant increase in dopamine levels with corresponding decline in its metabolites i.e., 3,4 dihydroxyphenylacetic acid and homovanilic acid. The aforementioned analysis is suggestive of preferential effect of 3b and 4d on MAO A and B, respectively in vivo. Hence, both of these compounds are suitable candidates for the development of MAO inhibition based therapy for the management of depression and Parkinson’s disease.