Jugal V. Mehta

Synthesis of 1,3,5-trisubstituted pyrazoline derivatives and their applications

A series of 1,3,5-trisubstituted pyrazolines based homoleptic Ru(III) complexes of type [Ru(L1–7)3]·(PF6)3 (L1–7 = pyrazoline ligands) have been synthesized and characterized by elemental analysis, electronic spectroscopy, conductance measurements, thermogravimetric analysis (TGA), electron paramagnetic resonance (EPR), fourier transform infrared (FT-IR) spectroscopy and liquid chromatography mass spectroscopy (LC-MS). Octahedral geometry around ruthenium has been assigned in all complexes using EPR and electronic spectral analysis. All complexes have been investigated for their interaction with Herring Sperm (HS) DNA utilizing an absorption titration (Kb = 2.42–6.07 × 105 M−1) and viscosity measurement study. The studies suggest the classical intercalative mode of binding. The DNA-binding property of the Ru(III) complexes was also investigated theoretically using a molecular docking study and suggests an intercalation binding mode between the complex and nucleotide base pairs. A cleavage study on pUC19 DNA has been performed by agarose gel electrophoresis. The results indicated that the Ru(III) complexes can more effectively promote the cleavage of plasmid DNA. The free ligands and their complexes have been evaluated for cytotoxicity activity against S. pombe cells at a cellular level. A comparative study of cellular level cytotoxicity values of the all compounds indicates that the metal complexes show better activity against S. pombe cells compared to the pyrazoline ligands. The complexes have been screened for their in vitro antibacterial activity against two Gram(+ve) and three Gram(−ve) microorganisms. Ru(III) complexes are good in vitro cytotoxic agents and 50% lethal concentration (LC50) values are in range of 5.296–7.925 μg mL−1. All newly synthesized Ru(III) complexes have been also evaluated for their in vitro antimalarial activity against Plasmodium falciparum strain [inhibition concentration (IC50) = 0.54–0.92 μg mL−1].

Antimalarial, antimicrobial, cytotoxic, DNA interaction and SOD like activities of tetrahedral copper(II) complexes

The mononuclear copper(II) complexes with P, O-donor ligand and different fluoroquinolones have been synthesized and characterized by elemental analysis, electronic spectra, TGA, EPR, FT-IR and LC-MS spectroscopy. An antimicrobial efficiency of the complexes has been tested against five different microorganisms in terms of minimum inhibitory concentration (MIC) and displays very good antimicrobial activity. The binding strength and binding mode of the complexes with Herring Sperm DNA (HS DNA) have been investigated by absorption titration and viscosity measurement studies. The studies suggest the classical intercalative mode of DNA binding. Gel electrophoresis assay determines the ability of the complexes to cleave the supercoiled form of pUC19 DNA. Synthesized complexes have been tested for their SOD mimic activity using nonenzymatic NBT/NADH/PMS system and found to have good antioxidant activity. All the complexes show good cytotoxic and in vitro antimalarial activities.

DNA interaction, cytotoxicity, antibacterial and antituberculosis activity of oxovanadium(IV) complexes derived from fluoroquinolones and 4- hydroxy-5-((4-hydroxyphenyl)diazenyl)thiazole- 2(3H)-thione†

Oxovanadium complexes (5a–5g) with fluoroquinolone ligands and azodye rhodanine (4-hydroxy-5-((4-hydroxyphenyl)diazenyl)thiazole-2(3H)-thione) were synthesized and the effect of different groups was studied, which displayed various biological and medicinal activities. The newly formed compounds were characterized using ESI-MS, UV-vis, IR, ESR spectroscopy, elemental analysis and molar electric conductivity. The in vitro antibacterial activity of the complexes against three Gram negative and two Gram positive microorganisms was studied and compared to the activity of free ligand and it shows considerable results. The minimum inhibitory concentration (MIC) of the compounds against Mycobacterium tuberculosis was determined and among all the complexes, 5c and 5d showed potency. The in vitro cytotoxicity of the complexes was determined with a brine shrimp bioassay and the LD50 obtained is in the range of 4–12 μg mL−1. The DNA binding activity was studied using UV-vis titration and viscosity measurements, and 5c has the highest binding constant value (6.91 × 105 M−1). DNA nuclease activity was studied using the agarose gel electrophoresis method and the compounds show 70–80% cleavage.

Design, synthesis and biological evaluation of pyrazoline nucleus based homoleptic Ru(III) compounds

A series of tri-substituted pyrazoline nucleus based homoleptic Ru(III) complexes of type [Ru(L1–7)2]·(PF6)3 (L1–7= heterocyclic pyrazoline derivatives) were synthesized and characterized by elemental analysis, their electronic spectra, conductance measurements, thermo gravimetric analysis (TGA), electron paramagnetic resonance (EPR), Fourier transform infrared (FT-IR) spectroscopy and mass spectrometry (MS). An octahedral geometry around ruthenium was assigned in all complexes using electronic spectral analysis and EPR measurements. All compounds were evaluated for cytotoxicity activity against S. pombe cells at a cellular level. A comparative study of cellular level cytotoxicity values of all the compounds indicated that all the metal complexes showed better activity against S. pombe cells compared to the free heterocyclic pyrazoline ligand. All the complexes were good in vitro cytotoxic agents and LC50 values were in the 5.57–8.01 mg L−1 range. They were also screened for their in vitro antimicrobial behavior against five different microorganisms. Inspection of their interaction with Herring Sperm (HS) DNA with an absorption titration (Kb = 0.37–5.02 × 105 L mol−1) and viscosity measurement study and suggested the classical intercalative mode of DNA binding. Moreover, the DNA-binding property of all the compounds were examined theoretically using a molecular docking study and suggested an intercalation binding mode between complex and nucleotide base pairs of DNA. The cleavage study on pUC19 DNA was checked by agarose gel electrophoresis. All newly synthesized compounds were also evaluated for their in vitro antimalarial study against the Plasmodium falciparum strain (IC50 = 0.46–1.50 mg L−1).

Biological applications of pyrazoline-based half-sandwich ruthenium(III) coordination compounds

The inclusion of biologically active ligands into metal complexes deals much scope for the design of novel drugs with improved and targeted activity. Studies on such complexes indicate that new mechanisms of action are favorable when combining the bioactivity of the ligand with the properties inherent to the metal, leading to the possibility of overcoming current drug resistance pathways. It is well known that deoxyribonucleic acid (DNA) is an important target in the organism for some metal-based drugs or reagents. These reagents can interact with DNA thereby changing the replication of DNA and inhibiting the growth of the tumor cells. It has been reported that the metal complexes can interact with DNA non-covalently in the mode of intercalation, groove binding, and electrostatic effect. Ruthenium complexes are also assumed to have a biological mode of action that is significantly dissimilar from those of platinum-based drugs. Additionally, the rich synthetic chemistry, redox accessible oxidation states, favorable ligand substitution reactions, and diverse coordination geometries of ruthenium complexes have been valuably considered for the design of new pharmaceutical agents. Ruthenium-based organometallic compounds are progressively gaining importance as promising aspirants for the design of novel and more effective metal-based drugs (Fricker, 2007). The antitumor activity of many organometallic ruthenium complexes is generally related to their enhanced DNAbinding affinity, which involves covalent coordination or simultaneous intercalation of extended aromatic groups and specific hydrogen bonding depending on the particular type of ligands used. In this regard, diverse ligand types are increasingly being developed and combined with the ruthenium(III)–pentamethylcyclopentadienyl ring moiety to enhance their DNA-binding properties, so as to achieve different biological functions and to maximize their effectiveness as therapeutic agents. The half-sandwich ruthenium(III) complexes with pyrazoline ligand show comparison and contrasts to many of the systems such as the actinomycins, porphyrins, Hoechst, and benzo[a]pyrene derivatives and others in forming complexes with the DNA or nucleic acids (Agarwal, Chadha, & Mehrotra, 2015; Basu & Suresh Kumar, 2016; Bathaie, Ajloo, Daraie, & Ghadamgahi, 2015; Jeon, Jin, Kim, & Lee, 2015; Monaselidze et al., 2015; Nagaraj, Ambika, & Arunachalam, 2015). Heterocyclic compounds have so far been synthesized mainly due to the wide range of biological activities. Much attention has been paid to the synthesis of heterocyclic compounds bearing nitrogen containing ring system, like pyrazole mainly due to their higher pharmacological activity. Pyrazole and its derivatives are the important structural motifs in heterocyclic chemistry and occupy significant location in medicinal chemistry. They exhibited a broad spectrum of pharmacological activities (Mehta, Gajera, & Patel, 2016). In the present study, a series of pyrazoline-based half-sandwich organometallic ruthenium complexes have been synthesized and well characterized. The synthesis and structural characterization of compounds were carried out with an aim to study their biological activity. A satisfactory property of this type of ruthenium complexes is the convenient piano-stool shape conferred by the metal center. Such a characteristic provides considerable opportunities for making new compounds with stimulating biological properties through functionalization and rational ligand design. All synthesized complexes were evaluated for their biological applications like DNA binding, DNA cleavage, antimalarial, antimicrobial, and cellular level cytotoxicity. These studies mainly focuses on exploring the trend in DNA-binding affinities of organometallic ruthenium complexes and the important differences in some related properties.

Half-sandwich iridiumIII complexes with pyrazole-substituted heterocyclic frameworks and their biological applications

Low-spin IrIII organometallic half-sandwich complexes of type [(η5-C5Me5)Ir(XY)Cl]+ (XY = bipyrazoles (4a–4b)/pyrimidin-2-amines (5a–5b)/triazolo[1,5-a]pyrimidines (6a–6b)) have been synthesized and characterized. All the newly synthesized compounds have been evaluated for their DNA binding properties with calf thymus (CT DNA), which revealed enhancement in the binding constant (Kb) of the complexes. The compounds bearing an imidazole substituent proved to be better binders than compounds containing a phenoxy linkage. Molecular docking attests that π–π stacking interactions have been observed between the receptor and the compounds. Furthermore, the observed DNA cleavage potency has been ascribed to a multitarget mechanism of action of these compounds. Intriguingly, the chelation of ligands with IrIII led to a remarkable enhancement of antibacterial activity against the arbitrarily selected two Gram +ve and three Gram −ve bacterial strains. The complexes of triazolo[1,5-a]pyrimidines proved to be the most cytotoxic compounds towards brine shrimp and S. pombe cells compared to pyrazole-containing heterocyclic frameworks. All complexes showed potent cytotoxicity as compared to the ligands, with IC50 values ranging from 78 to 234 μM toward A549 human lung cancer cells. The potency of the compounds toward these cancer cells was in the order pyrimidin-2-amines > bipyrazoles > triazolopyrimidines.

Biological assessment of substituted quinoline based heteroleptic organometallic compounds

A series of substituted quinoline derivatives were synthesized via the Friedlander condensation reaction, using substituted 2-aminobenzophenone with 2-acetyl pyridine or 2-acetyl thiophene in the presence of sodium methoxide. The series of substituted quinoline based organometallic ruthenium complexes of the type [(Cp*)Ru(Ln)Cl]·Cl (where, Cp* = the pentamethylcyclopentadienyl ring, Ln = L1–7 = quinoline ligands) were synthesized and characterized by elemental analysis, electronic spectra, conductance measurements, thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) and mass spectrometry. They are known as piano stool complexes, due to the similarity of their structures to a piano stool, and the metal centre is coordinated by a pentamethylcyclopentadienyl ring, chlorido ligand and chelating quinoline ligand. All the compounds were investigated for their in vitro antimicrobial activity against five different bacterial strains, and their interaction with herring sperm (HS) DNA; absorption titration (Kb = 0.34–6.25 × 105 L mol−1) and viscosity measurements were also carried out. From the studies, we conclude that the complexes display the classical intercalative mode of DNA binding. The DNA-binding properties of all the compounds were also examined theoretically, using a molecular docking study, which proved the intercalation binding mode between compounds and nucleotide base pairs of HS DNA. The capability of the compounds to cleave pUC19 DNA was examined by chemical nuclease activity. The results indicate that the ruthenium complexes promote the cleavage of plasmid DNA more effectively than the respective quinoline ligands. All the compounds were evaluated for cytotoxicity activity against S. pombe cells at the cellular level and exhibited enhanced activity against S. pombe cells, compared to the quinoline ligands. All synthesized compounds were also evaluated for their in vitro antimalarial activity [50% inhibition concentration (IC50) = 0.55–1.84 mg L−1] against the Plasmodium falciparum strain, as well as in vitro cytotoxic activity [50% lethal concentration (LC50) = 5.64–119.67 mg L−1] against brine shrimp (Artemia cysts) eggs.