شریعت کی حقیقت اور تعبیرات: افکارِ مجدد الف ثانی کا ایک فنی زاویہ نگاہ

When we analyse the preaching of religion by the Holy Prophets (peace an blessing of Allah be upon them) in the background of history of mankind, we come to know that Allah Almighty offered at least a Shari'ah (a code of social, moral and religious conduct) to every Prophet or bound them to a Shari'ah previousl preached by another Prophet before them. Shari'ah is, in fact, based upon the principles and practices to lead life. There had been at least some differences in the Shari'ah different Prophets with regard to the difference of their time and place. It is a proven fact that the followers of a Prophet had always been bound to follow the Shari'ah of their own Prophets. The Shareeya of the Prophet of Islam (peace and blessing of Allah be upon him) is absolutely consummate in every respect and it also fulfills the needs of all times to come. It is because of the fact that Mujtahidin who kept on resorting to Ijtehad. The topic under consideration is an intellectual research analysis of the efforts of Shaykh Ahmad Sirhindi in the field of Ijtehad in the history of Islam.

Synthesis Characterization and Pharmacological Screening of Sulfonated Derivatives of Piroxicam

Medicinal chemistry is a discipline associated with the designing, synthesis, and development of drugs used in different pathophysiological conditions. Small organic compounds or biologics are mostly studied in medicinal chemistry but the key focus is on small molecules to develop new synthetic agents for human use. These small molecules are usually heterocyclic compounds, hold a ring in their structure along with heteroatoms in addition to the carbon. Heterocyclic compounds are abundantly present in nature and very important from the therapeutic and economic point of view. Detailed information on the pharmacological activities of each organic compound is a challenge for the medicinal chemists because a large of number of synthetic organic compounds has been prepared currently. Therefore, the idea of structure activity relationship has been used to explain the variation in biological activity of organic compounds. Structure activity relationship is used in lead optimization to improve the efficacy and minimize the toxicity of the molecules. The biology oriented synthesis "BIOS" is a starting point for the search of new therapeutic agents. It is an approach for the generation of libraries of compounds for their biological applications. Non-steroidal anti-inflammatory drugs are an important class of organic compounds, having widespread applications in different diseases and most commonly used as analgesic, antipyretic and anti-inflammatory agents. They are used for the management of various acute and chronic inflammatory conditions alone or in combination with opioid analgesics. Oxicam is comparatively a new class of drugs consists of enolic acid compounds which possess analgesic and anti-inflammatory effects. Their structure contains 1, 2-benzothiazene nucleus, substituted at position-3 with carboxamide. Piroxicam belongs to the oxicam family discovered in 1972. It is the first member of this class and has marked analgesic and antipyretic properties and therefore, has been used clinically for the treatment of persistent inflammatory disorders for the last 30 years. Chemically, piroxicam is 4-hydroxy-2-methyl-2H-1, 2-benzothiazine-1-(N-(2 pyridinyl) carboxamide)-1, 1-dioxide. It is a heterocyclic compound and consists of benzene and thiazine rings. Benzo represents benzene while thiazine represents a six-membered ring in benzothiazine. It acts by blocking the cyclooxygenase enzymes and inhibiting the synthesis of prostaglandins. Due to the existence of enolic hydroxy (OH) group, piroxicam presented fascinating structural properties which prompted the medicinal chemists and pharmacologists for further research. The present study was designed to synthesize and characterize the piroxicam derivatives and screened them for in-vivo and in-vitro biological activities. Piroxicam derivatives (1-18) were prepared by dissolving piroxicam with commercially available alkyl/aryl sulfonyl chloride and triethylamine in tetrahydrofurane as a solvent, in a round bottom flask with constant stirring at room temperature. After the completion of the reaction, the resulting products were filtered, washed with hot n-hexane and excess of solvent was removed under vacuum at reduced pressure. Different spectroscopic procedures like 1H-NMR, EIMS, IR, UV and CHN analysis were used for structural elucidation of newly synthesized piroxicam derivatives and subjected to biological screening in order to prove that changing the substituent''s modifies the inhibitory potential of the individual derivative as an evident of structure activity relationship studies. The compounds were evaluated for the antinociceptive activity at 5, 10, 20 and 30 mg/kg doses. The compounds were found to be active in acetic acid induced writhing test but inactive in hot plate test for analgesia, indicating that the compounds only possess the peripheral mechanism and no central mechanism is involved as compared with standards piroxicam and tramadol respectively. Anti-inflammatory activity was determined in the carrageenan induced paw edema model in mice. The derivatives were tested at 10, 20 and 30 mg/kg doses and most of them were found to be significantly potent as compared with standard piroxicam. The piroxicam analogues when screened for the antipyretic effect in Brewer’s yeast induced pyrexia model in mice at 10, 20 and 30 mg/kg doses, the prominent antipyretic effects were observed as compared with standard paracetamol. The results showed that the compounds exhibited significant (*P < 0.05, **P < 0.01 and ***P < 0.001.) dose dependent antinociceptive, anti-inflammatory and antipyretic activities when compared with standards. The analogues were found to be safe in acute toxicity test at the doses of 50, 100 and 150 mg/kg i.p., and no gross mortality or behavioral changes were observed during 24 hours assessment time. The piroxicam derivatives were also screened for the different in-vitro activities. In in-vitro antiglycation assay, the compounds showed varying degree of antiglycation potential when compared with standard “rutin”. Compound 2, 4, and 7 exhibited excellent antiglycation activity with better potency than the reference. In in-vitro 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium cytotoxicity assay, piroxicam derivatives exhibited varying degree of cytotoxic activity against breast cancer cell lines when compared with standard “doxorubicin”. Compound 4, 17 and 18 showed moderate anticancer activity while compound 3 showed low growth inhibitory activity. The derivatives were also screened for the in-vitro immunomodulatory activity against the standard “ibuprofen”. None of the compound was found to be active in the in-vitro immunomodulatory activity. It concludes that, changing the substituent or changing the position of substituent on aromatic ring does not impart any activity to the compounds. Results of in-vitro dipeptidyl peptidase-IV inhibitory assay showed that the substitution does not noticeably change the activity of the compounds but impart a weak inhibitory activity to the compounds 1, 4, 11, 13 and 14. Other piroxicam derivatives of this series were inactive toward in-vitro dipeptidyl peptidase-IV inhibitory assay. In case of in-vitro leishmanicidal activity, compounds 7, 8, 10, 13, 14 and 17 showed good to low leishmanicidal activity while other compounds of this series having less than 100 % inhibition values and therefore concluded them as inactive. It can be concluded that, some piroxicam derivatives possess potent, good/low in-vitro antiglycation, anticancer, dipeptidyl peptidase-IV inhibitory and leishmanicidal potential as compared with standards but inactive in in-vitro immunomodulatory activity. Findings of this research work strongly support the use of piroxicam derivatives as analgesic, antipyretic, anti-inflammatory, anti-glycating, dipeptidyl peptidase-IV inhibitors, leishmanicidal and anticancer agents. However, further comprehensive research work on piroxicam derivatives as well as their use for selective inhibition of cyclooxygenase-2 enzyme is necessary in order to minimize the gastrointestinal complications.