World Peace in the Light of Sīrah of the Prophet Muḥammad SAW

The advancement in science and technology has made the world peace and prosperity very important at this time in the human history. We find in the human history, since it was recorded, that almost all the civilizations were very intolerant, brutal to their opponents, especially, to the believers of other religions. On the other hand, the Islamic states were the most tolerant and accommodating to other religions. This fact is proved from the early history of Islām during the period of the Prophet Muḥammad (r) and his immediate successors. Similar is the case in the later history of the Muslims, during the period of the Abbasid, the Umayyids in Spain, the Turks, the Mughal era and in the Far East. Human and economic losses in wars were very huge during the first, the second world wars, and the current wars being fought in Iraq and Afghanistan. The human and material losses are horrible. The author believes that the Prophet Muḥammad (r) ’s teachings and traditions of moderation, tolerance, human respect, freedom of religious practice are the only ways to peace and prosperity in the world.

Complexes of Ruthenium and Osmium Based on Oxicam Scaffold As Potential Anticancer Agents

Metal based drugs have been used for medicinal purposes since ages but their potential was realized after the discovery of the first metal based chemotherapeutic agent, i.e., cisplatin, which became one of the most successful anticancer drugs espcecially for the treatment of testicular cancer. Other members of this class include oxaliplatin, carboplatin and nedaplatin. The use of platinum based drugs is limited due to their adverse side effects (e.g., nephrotoxicity, neurotoxicity, nausea, vomiting etc.) and intrinsic or acquired resistance. These limitations prompted bioinorganic chemists to develop new strategies to treat cancer with other metal based anticancer agents with higher efficacy and lesser undesired effects. Therefore, different metal complexes of titanium, iron, cobalt, gallium, ruthenium and osmium etc. were investigated. Among these NAMI-A (imidazolium [tetrachlorido(dimethylsulfoxide)(1Himidazole)ruthenate(III)]), KP46 (trismaltolate gallium) and KP1019 (indazolium trans[tetrachloridobis(1H-indazole)ruthenate(III)]) have enteredclinical trials. On the other hand, Ru(II)/Os(II) half sandwich organometallic complexes increase the lipophilic character of complexes and facilitate their uptake into cells. RAPTA type complexes are among the most popular examples of half sandwich organometallics. Furthermore, the coordination of bioactive ligands with these established organometallic pharmacophores may enhance the efficacy of these biologically active compounds by altering their physicochemical and pharmacological properties. In particular, the use of bioactive ligands such as hydroxypyrones, quinolones and non-steroidal anti-inflammatory drugs (NSAIDs) often resulted in promising bioactivity of the compounds. In this thesis, the use of oxicam based NSAIDS as ligands for Ru(II) and Os(II) was investigated. For this purpose different series of ligands based on the oxicam scaffold were prepared. These include 1,2-benzothiazine based primary amides, secondary amides, indazole and methyl pyridyl based secondary amides, piroxicam as well as isoxicam analogues, 1,2-benzothiazine based α,βunsatuarated ketones and pyrazole based benzenesulfonamides. Furthermore, these ligands were reacted with Ru(II) and Os(II) cymene dimer to obtain organometallic complexes. All the ligands and complexes were characterized with different spectroscopic techniques including FT-IR, 1H, 13C NMR, elemental analysis, high resolution mass spectrometry and twenty seven compounds were analyzed by single crystal X-ray diffraction analysis. The cytotoxic activity of the complexes towards human colorectal carcinoma HCT116, non-small cell lung carcinoma NCIH460 and cervical carcinoma SiHa cells was investigated by using the sulforhodamine B (SRB) assay. The prepared ligands behaved as monodentate (N donor) or bidentate chelators (O,O-, N,O- and N,N-donor systems) depending upon the ligand structure as well as reaction conditions such as xxix nature of solvent used for reaction. The 1,2-benzothiazine based primary amides were synthesized by reacting compound 5 with different alkylating agents in basic conditions to isolate ligands 6a-g. These O,O-coordinating ligands were used to synthesize the organometallic ruthenium complexes 7a-g (Scheme-1) with piano-stool configuration. These complexes were evaluated for their anticancer activity and results indicate that only 7f and 7g were active against three different human cancer cell lines. On the other hand, 1,2-benzothiazine based secondary amides were synthesized by reacting compound 8 with different aniline derivatives to obtain O,O-chelating ligands 9a-g. When these ligands were reacted with [Ru(cym)Cl2]2, the same O,Ocoordination behavior was observed to stabilize metal complexes 10a-g by forming sixmembered rings and giving rise to piano stool type geometry (Scheme-2). All these complexes were found active against different anticancer cell lines and the most lipophilic compound was found the most active with an IC50 value of 13.58 µM. The N-benzyl analogues of piroxicam and isoxicam 11 and 12 were also prepared and reacted with MII(η6-p-cymene). Compounds 11 and 12 can act as monodentate ligands through their pyridyl/isoxazolyl nitrogen atom and as bidentate chelators to Ru(II) and Os(II) metal ions by forming six membered rings through pyridyl/isoxazolyl nitrogen and the amide oxygen atoms (Scheme-3). In compounds 15-18 functionalization at position 3 was carried out to get indazolyl/pyridyl goup-containing oxicam analogues which act as monodentate ligands and coordinate to ruthenium/osmium centres through pyridyl/indazolyl nitrogens. The results of anticancer activity studies revealed that organo-Ru(II) and -Os(II) complexes 18a-c are more active than the free ligand 18 (Scheme-4). The 1,2-benzothiazine based chalcones (Scheme-5) were obtained as intermediates which were reacted with hydrazine to isolate 1,2-benzothiazine based pyrazole containing sulphonamide ligands 21a-j. The results of anticancer activity assays show that halogen containing derivatives are more active in this series (Scheme-6). These pyrazole containing sulphonamides were reacted with [Ru(cym)Cl2]2 to isolate complexes in which these sulfonamides acted either asmonodentate or bidentate ligands. In complexes 22a-k ligands coordinated mondentately through the pyrazole nitrogen (Scheme-7) while in complexes 23a-g they coordinated bidentately via pyrazole and sulphonamide nitrogen atoms by forming rather stable seven membered rings (Scheme-8). The biological investigations indicate moderate to high IC50 values for these complexes and it was also observed that within the series of compounds, the most lipophilic complex was the most active.