Pyrazoles are widely used as core motifs for a large number of compounds for various applications such as catalysis, agro-chemicals, building blocks of other compounds and in medicine. The attractiveness of pyrazole and its derivatives is their versatility that allows for synthesis of a series of analogues with different moieties in them, thus affecting the electronics and by extension the properties of the resultant compounds. In medicine pyrazole is found as a pharmacophore in some of the active biological molecules. While pyrazole derivatives have been extensively studied for many applications including anticancer, antimicrobial, anti-inflammatory, antiglycemic, anti-allergy and antiviral, much less has been reported on their metal counterparts in spite of the fact that metals have been shown to impart activity to ligands. Thus this perspective is intended to demonstrate the potential of pyrazole and pyrazolyl metal complexes in the areas of drug discovery and development. Several examples, that include palladium, platinum, copper, gold, zinc, cobalt, nickel, iron, copper, silver and gallium complexes, are used to bolster the above point. For the purposes of this review three areas are discussed, that is pyrazole metal complexes as: (i) anticancer, (ii) antibacterial/parasitic and (iii) antiviral agents.

The reactions of potassium salts of the dithiocarbamates L {where L = pyrazolyldithiocarbamate (L1), 3,5-dimethylpyrazolyldithiocarbamate (L2), or indazolyldithiocarbamate (L3)} with the gold precursors [AuCl(PPh3)], [Au2Cl2(dppe)], [Au2Cl2(dppp)], or [Au2Cl2(dpph)] lead to the new gold(I) complexes [AuL(PPh3)] (1–3), [Au2L2(dppe)] (4–6), [(Au2L2)(dppp)] (7–9), and [Au2(L)2(dpph)] (10–12) {where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, and dpph = 1,6-bis(diphenylphosphino)hexane}. These gold compounds were characterized by a combination of NMR and infrared spectroscopy, microanalysis, and mass spectrometry; and in selected cases by single-crystal X-ray crystallography. Compounds 4–6, which have dppe ligands, are unstable in solution for prolonged periods, with 4 readily transforming to the Au18 cluster [Au18S8(dppe)6]Cl2 (4a) in dichloromethane. Compounds 1–3 and 7–12 are all active against human cervical epithelioid carcinoma (HeLa) cells, but the most active compounds are 10 and 11, with IC50 values of 0.51 μM and 0.14 μM, respectively. Compounds 10 and 11 are more selective toward HeLa cells than they are toward normal cells, with selectivities of 25.0 and 70.5, respectively. Further tests, utilizing the 60-cell-line Developmental Therapeutics Program at the National Cancer Institute (U.S.A.), showed 10 and 11 to be active against nine other types of cancers.

The reactions of 2,6-bis(3,5-dimethylpyrazol-1-ylmethyl)pyridine (L1) and 2,6-bis(3,5-di-tert-butylpyrazol-1-ylmethyl)pyridine (L2) with NiCl 2 or NiBr 2 gave the nickel(II) complexes [NiCl 2 (L1)] (1), [NiBr 2 (L1)] (2), [NiCl 2 (L2)] (3), and [NiBr 2 (L2)] (4) in high yields. Compounds 2-(3,5-dimethylpyrazol-1-ylmethyl)pyridine (L3) and 2-(3,5-di-tert-butylpyrazol-1-ylmethyl)pyridine (L4) on the other hand gave either mononuclear or dinuclear nickel(II) complexes, depending on the steric bulk of the substituents on the pyrazolyl unit. While L3 gave the dinuclear complexes [Ni 2 (µ 2 -Cl) 2 Cl 2 (L3) 2 ] (5) and [Ni 2 (µ 2 -Br) 2 Br 2 (L3) 2 ] (6), L4 gave the mononuclear complexes [NiCl 2 (L4)] ( 7) and [NiBr 2 (L4)] ( 8). Activation of 1-8 with EtAlCl 2 resulted in the oligomerization of ethylene to C 4 , C 6 , and C 8 alkenes, followed by subsequent Friedel-Crafts alkylation of the toluene solvent. Activities as high as 15 660 kg of alkylated products/mol Ni/h were observed for 5 at 40 bar. However, when hexane was used as solvent, only trace amounts of alkylated toluene products were observed.

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A range of monomeric tetra-coordinate copper (II) and zinc (II) complexes based on N,O-bidentate salicylaldimine Schiff base ligands has been synthesized and characterized using various spectroscopic techniques. These complexes were then evaluated as initiators in ring-opening polymerization of lactides at both 70• C and 110• C. The effect of structural changes in the complexes on the ability of these compounds to initiate lactide polymerization as well as the impact on the chemical and physical characteristics of the polymers obtained indicate that the coordination geometry of the metal complex, M-O bond length and substituents on the Schiff base ligand all play a role in the catalyst activity. Electronic factors were dominant in the case of the copper complexes while steric factors prevailed in the case of Zn initiators. Both the Zn and Cu complexes exhibit characteristics of living ring opening polymerization.

The oxidation of L-cysteine and its metabolites cystine and L-cysteinesulfinic acid by chlorite and chlorine dioxide has been studied in unbuffered neutral and slightly acidic media. The stoichiometry of the oxidation of L-cysteine was deduced to be 3ClO 2 -+ 2H 2 NCH(COOH)CH 2 SH f 3Cl -+ 2H 2 NCH(COOH)CH 2 SO 3 H with the final product as cysteic acid. The stoichiometry of the chlorite-cysteinesulfinic acid gave a ratio of 1:2, ClO 2 -+ 2H 2 NCH(COOH)CH 2 SO 2 H f Cl -+ 2H 2 NCH(COOH)CH 2 SO 3 H. There was no further oxidation past cysteic acid, and there was no evidence of sulfate formation which would have indicated the cleavage of the carbon-sulfur bond. The reaction is oligooscillatory in chlorine dioxide formation. In conditions of excess oxidant, the reaction is characterized by a short induction period followed by a rapid and autocatalytic formation of chlorine dioxide. Chlorine dioxide is formed by the reaction of intermediate HOCl with the excess chlorite: 2ClO 2 -+ 2HOCl + H + f 2ClO 2 (aq) + Cl -+ H 2 O. Oligooscillations observed in chlorine dioxide formation result from the competition between this pure oxyhalogen reaction and reactions that consume chlorine dioxide. The rate of the reaction of chlorine dioxide with cysteine and its metabolites is fast and is of comparable magnitude with the reactions that form chlorine dioxide. The reaction of chlorine dioxide with L-cysteine is first order in both oxidant and substrate, retarded by acid, and has a lower-limit bimolecular rate constant of 405 ( 50 M -1 s -1 , while for the reaction with L-cysteinesulfinic acid the rate constant is 210 ( 15 M -1 s -1 . It would appear that the existence of a zwitterion on the asymmetric carbon atom precludes the formation of N-chloramines as has been observed with taurine and aminomethanesulfonic acid. The mechanism for the reaction is satisfactorily described by a network of 28 elementary reactions which include autocatalysis by HOCl.

Collectively, this in vitro study provides insights into action of palladium and platinum complexes and demonstrates the potential use of these compounds, and in particular complex 3, in the development of new anticancer agents.