Synthesis,spectral investigation and development of tetrahedral copper(II) complexes as artificial metallonucleases and antimalarial agents

Seven new copper(II) complexes of type [Cu(A)(L)]?H₂O (A = sparfloxacin, ciprofloxacin, levofloxacin, gatifloxacin, pefloxacin, ofloxacin, norfloxacin; L = 5‐[(3‐chlorophenyl)diazenyl]‐4‐hydroxy‐1,3‐thiazole‐2(3H)‐thione) were synthesized and characterized using elemental and thermogravimetric analyses, and electronic, electron paramagnetic resonance (EPR), Fourier transform infrared and liquid chromatography–mass spectroscopies. Tetrahedral geometry around copper is assigned in all complexes using EPR and electronic spectral analyses. All complexes were investigated for their interaction with herring sperm DNA utilizing absorption titration (K_b = 1.27–3.13 × 10⁵ M^?1) and hydrodynamic volume measurement studies. The studies suggest the classical intercalative mode of DNA binding. The cleavage reaction on pUC19 DNA was monitored by agarose gel electrophoresis. The results indicate that the Cu(II) complexes can more effectively promote the cleavage of plasmid DNA. The superoxide dismutase mimic activity of the complexes was evaluated by nitroblue tetrazolium assay, and the complexes catalysed the dismutation of superoxide at pH = 7.8 with IC₅₀ values in the range 0.597–0.900 μM. The complexes were screened for their in vitro antibacterial activity against five pathogenic bacteria. All the complexes are good cytotoxic agents and show LC₅₀ values ranging from 5.559 to 11.912 µg ml^?1. All newly synthesized Cu(II) complexes were also evaluated for their in vitro antimalarial activity against Plasmodium falciparum strain (IC₅₀ = 0.62–2.0 µg ml^?1). Copyright © 2015 John Wiley & Sons, Ltd.     

Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.     

Path to achieving molecular dispersion in a dense reactive mixture

A uniform dispersion of reactants is necessary to achieve a complete reaction involving multicomponents. In this study, we have examined the role of plasticizer in the reaction of two seemingly unlikely reactants: a highly crystalline hexamethylenetetramine (HMTA) and a strongly hydrogen bonded phenol formaldehyde resin. By combining information from NMR, infrared spectroscopy and differential scanning calorimetry, we were able to determine the role of specific intermolecular interactions necessary for the plasticizer to dissolve the highly crystalline HMTA and to plasticize the phenol formaldehyde resin in this crosslinking reaction. The presence of the plasticizer increased the segmental mobility, disrupted the hydrogen bonded matrix, and freed the hydroxyl units, which further increased the solubility of the HMTA. Both the endothermic and exothermic transitions are accounted for in the calorimetric data obtained. For the first time, it is possible to obtain the effective molar ratio of each component needed to complete the crosslinking reaction efficiently. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 1519–1526     

Antimicrobial activity on the copolymers of 2,4‐dichlorophenyl methacrylate with methyl methacrylate: Synthesis and characterization

Copolymers of monomers 2,4‐dichlorophenyl methacrylate (2,4‐DMA) and methyl methacrylate (MMA) were synthesized with different monomer feed ratios using toluene as a solvent and 2,2′‐azobisisobutyronitrile (AIBN) as an initiator at 70 °C. The copolymers were characterized by IR‐spectroscopy, and copolymer composition was determined with UV‐spectroscopy. The linearization method of Fineman–Ross was employed to obtain the monomer reactivity ratios. The molecular weights and polydispersity indexes were determined by gel permeation chromatography (GPC). Thermogravimetric analyses of polymers were carried out in nitrogen atmosphere. The homo‐ and copolymers were tested for their antimicrobial properties against selected microorganisms. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 5227–5234, 2004     

An efficient electrophilic N-amination utilizing in situ generated chloramine under phase transfer conditions

An efficient, one-pot, phase transfer N-amination technology was developed. The protocol utilizes chloramine, an inexpensive and safe electrophilic aminating agent potentially viable for commercial manufacturing.     

Active-constraint variable ordering for faster feasibility of mixed integer linear programs

The selection of the branching variable can greatly affect the speed of the branch and bound solution of a mixed-integer or integer linear program. Traditional approaches to branching variable selection rely on estimating the effect of the candidate variables on the objective function. We present a new approach that relies on estimating the impact of the candidate variables on the active constraints in the current LP relaxation. We apply this method to the problem of finding the first feasible solution as quickly as possible. Empirical experiments demonstrate a significant improvement compared to a state-of-the art commercial MIP solver.     

Diastereoselective formation of 2-aryl-3-arenesulfonyl 4-ethyl-1,3-oxazolidines: An X-ray crystallographic and H NMR study

N-Arylsulfonamides of (R)- and (S)-2-amino-1-butanol, on condensation with aromatic aldehydes produced diastereomerically pure 2-aryl-3-arenesulfonyl 4-ethyl-1,3-oxazolidines. The absolute configurations of one enantiomeric pair have been determined from two fully refined X-ray structures, supplemented by nmr data.