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The versatile structural motif of hydroxypyrone is found in natural products and can be easily converted into hydroxypyridone and hydroxythiopyridone analogues. The favourable toxicity profile and ease of functionalization to access a vast library of compounds make them an ideal structural scaffold for drug design and discovery. This versatile scaffold possesses excellent metal chelating properties that can be exploited for chelation therapy in clinics. Deferiprone [1,2-dimethyl-3-hydroxy-4(1

The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2-pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components.

Anticancer-active RuII -η6 -p-cymene complexes of bioactive 2-pyridinecarbothioamide ligands have been shown to have high selectivity for plectin and can be administered orally. Reported herein is the functionalization of a 2-pyridinecarbothioamide with a sulfonamide group and its conversion into M-η6 -p-cymene complexes (M = Ru, Os). The presence of a sulfonamide moiety in many organic drugs and metal complexes endows these agents with interesting biological properties and can transform the latter into multi-targeted agents. The compounds were characterized with standard methods and the in vitro anticancer activity data was compared with studies on the hydrolytic stability of the complexes and their reactivity to small biomolecules. A molecular modeling study revealed plausible modes of binding of the complexes in the catalytic pocket of carbonic anhydrase II.

Ru(II) and Os(II) complexes of 2-pyridinecarbothioamide ligands were introduced as orally administrable anticancer agents (S.M. Meier, M. Hanif, Z. Adhireksan, V. Pichler, M. Novak, E. Jirkovsky, M.A. Jakupec, V.B. Arion, C.A. Davey, B.K. Keppler, C.G. Hartinger, Chem. Sci., 2013, 4, 1837-1846). In order to identify structure-activity relationships, a series of N-phenyl substituted pyridine-2-carbothiamides (PCAs) were obtained by systematically varying the substituents at the phenyl ring. The PCAs were then converted to their corresponding RuII(η6-p-cymene) complexes and characterized spectroscopically and by X-ray diffraction as well as in terms of stability in water and HCl. The cytotoxic activity of the PCA ligands and their respective organoruthenium compounds was evaluated in a panel of cell lines (HCT116, H460, SiHa and SW480). The lipophilic PCAs 1-4 showed cytotoxicity in the low micromolar range and 6 was the most potent compound of the series with an IC50 value of 1.1μM against HCT116 colon cancer cells. These observations were correlated with calculated octanol/water partition coefficient (clogP) data and quantitative estimated druglikeness. A similar trend as for the PCAs was found in their Ru complexes, where the complexes with more lipophilic ligands proved to be more cytotoxic in all tested cell lines. In general, the PCAs and their organoruthenium derivatives demonstrated excellent drug-likeness and cytotoxicity with IC50 values in the low micromolar range, making them interesting candidates for further development as orally active anticancer agents.

Human biomonitoring (HBM) measures the concentration levels of substances or their metabolites in human body fluids and tissues. HBM of dose and biochemical effect monitoring is an effective way of measuring human exposure to chemical substances. Many countries have conducted HBM studies to develop a data base for many chemicals including trace metals of health concern for their risk assessment and risk management. However, in Pakistan, HBM program on large scale for general population does not exist at present or in the past has been reported. Various individual HBM studies have been reported on the assessment of trace elements (usually heavy metals) from Pakistan; most of them are epidemiological cross sectional surveys. In this current review we tried to develop a data base of HBM studies of trace elements namely arsenic, cadmium, copper, chromium, iron, lead, manganese, nickel, and zinc in biological fluids (blood, urine) and tissues (hair, nails) in general population of Pakistan. Studies from all available sources have been explored, discussed and presented in the form of tables and figures. The results of these studies were critically compared with large scale HBM programs of other countries, (US & European communities etc). It was observed from the present study that the most of the toxic metals in biological fluids/tissues in general population of Pakistan, have higher background values comparatively. For example the mean values of toxic metals like As, Cd, Cr, Ni, and Pb in blood of general population were found as 2.08 μg/L, 4.24 μg/L, 60.5 μg/L, 1.95 μg/L, 198 μg/L respectively. Similarly, the urine mean values of 67.6 μg/L, 3.2 μg/L, 16.4 μg/L, 6.2 μg/L and 86.5 μg/L were observed for As, Cd, Cr, Ni, and Pb respectively.

Starting from ibuprofen, a non-steroidal anti-inflammatory drug, N,N’-disubstituted thiourea derivatives were synthesized by refluxing the acid chloride of ibuprofen with potassium thiocyanate followed by substituted anilines to get N-2-(4-(2-methylpropyl)phenyl)propionoyl-N’-(2’-bromophenyl) thiourea (1), N-2- (4-(2-methylpropyl)phenyl)propionoyl-N’-(2’-chlorophenyl) thiourea (2) and N-2-(4-(2-methylpropyl)phenyl)propionoyl-N’-(3’,4’-dichlorophenyl) thiourea (3). Metal complexes (4-15) of (1-3) were synthesized by refluxing it with one equivalence salts of Co (ΙΙ), Ni(II), Pb(II) and Cu(I). Structures of all the synthesized thiourea ligands and their metal complexes were determined by FTIR and 1HNMR spectroscopy. Shift in stretching frequency in FTIR and resonance frequency in 1HNMR spectroscopic data suggested that the ligands and metal are coordinated to afford respective metal complexes M[L]n. The synthesized compounds were tested against urease enzyme and the results were compared with standard thiourea, as positive control. Most of the investigated compounds showed potential inhibitory activity against Jack bean urease. Compound 5 was found to be the most potent urease inhibitor with IC50 of 14.6 μΜ, whereas compounds 8, 11 and 12 possessed potent urease inhibition. The tested compounds can be taken as lead molecules for gastrointestinal ulcer therapy.

Ru(II) and Os(II) complexes of 2-pyridinecarbothioamide ligands were introduced as orally administrable anticancer agents (S.M. Meier, M. Hanif, Z. Adhireksan, V. Pichler, M. Novak, E. Jirkovsky, M.A. Jakupec, V.B. Arion, C.A. Davey, B.K. Keppler, C.G. Hartinger, Chem. Sci., 2013, 4, 1837-1846). In order to identify structure-activity relationships, a series of N-phenyl substituted pyridine-2-carbothiamides (PCAs) were obtained by systematically varying the substituents at the phenyl ring. The PCAs were then converted to their corresponding Ru

Trace heavy metals, such as arsenic, cadmium, lead, chromium, nickel, and mercury, are important environmental pollutants, particularly in areas with high anthropogenic pressure. In addition to these metals, copper, manganese, iron, and zinc are also important trace micronutrients. The presence of trace heavy metals in the atmosphere, soil, and water can cause serious problems to all organisms, and the ubiquitous bioavailability of these heavy metal can result in bioaccumulation in the food chain which especially can be highly dangerous to human health. This study reviews the heavy metal contamination in several areas of Pakistan over the past few years, particularly to assess the heavy metal contamination in water (ground water, surface water, and waste water), soil, sediments, particulate matter, and vegetables. The listed contaminations affect the drinking water quality, ecological environment, and food chain. Moreover, the toxicity induced by contaminated water, soil, and vegetables poses serious threat to human health.