Marilyn Daisy Milton

Synthesis of 2-aryl/heteroaryloxazolines from nitriles under metal- and catalyst-free conditions and evaluation of their antioxidant activities.

The synthesis of structurally diverse 2-aryl/heteroaryloxazolines from nitriles and aminoalcohols has been achieved under metal- and catalyst-free conditions in good to excellent yields. An array of functional groups are well-tolerated, thus, allowing the introduction of many important biologically active motifs such as azoles, ring-fused azoles, saturated heterocyclics, and amines in 2-aryloxazoline scaffolds. An evaluation of the antioxidant properties using the DPPH (diphenyl picryl hydrazyl) assay method shows the pyrrole-functionalized 2-aryloxazoline to be the best antioxidant among all the synthesized 2-aryl/heteroaryloxazolines.

Synthesis of [DTPA-bis(D-ser)] chelate (DBDSC): an approach for the design of SPECT radiopharmaceuticals based on technetium.

D-Serine is a physiological coagonist of the N-methyl D-aspartate (NMDA) type of glutamate receptor-a key excitatory neurotransmitter receptor in the brain. D-Serine appears to be a part of the synapse through a variety of transporters located on both neurons and astrocytes. The development of 99mTc radiolabeled amino acid based radiopharmaceuticals for imaging a variety of tumors has found to be useful in diagnostic imaging. Diethylene triamine penta acetic acid (DTPA) is one of the most well-known chelating reagent for the production of stable complexes with various heavy metal ions. We have synthesized [DTPA-bis(D-ser)] in 90% yield and analyzed the chelate by spectroscopic techniques. The DBDSC chelate binds to 99mTc with high efficiency at ambient temperature. The resulting chelate is stable under physiological conditions (37oC, pH=7.4) for at least 24 h after radiocomplexation. The receptor binding studies of 99mTc-[DTPA-bis(D-ser)] in established lung adeno carcinoma A549 exhibited Kd value to be 26nM. A549 Tumor in athymic mice was accumulated in the γ-images. The major accumulation of the radiotracer was observed in tumor, followed by kidneys. 99mTc-[DTPA-bis(D-ser)] has promising utility as SPECT-radiopharmaceutical.

Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis

Neuropathological cascades leading to reduced cholinergic transmission in Alzheimer’s disease led to development of AChE-inhibitors. Although lethal dose of some inhibitors cause interruption with AChE mediated mechanism but reversible AChE inhibitors can assist in protection from inhibition of AChE and hence in an aim to probe potential molecules as anticholinesterase and as reactivators, computationally structure-based approach has been exploited in this work for designing new 2-amino-3-pyridoixime-dipeptides conjugates. We have combined MD simulations with flexible ligand docking approach to determine binding specificity of 2-amino-3-pyridoixime dipeptides towards AChE (PDB 2WHP). PAS residues are found to be responsible for oxime-dipeptides binding along with π–π interactions with Trp86 and Tyr286, hydrogen bonding with side chains of Asp74 and Tyr341 (Gscore –10.801 and MM-GBSA free energy –34.89 kcal/mol). The docking results depicted complementary multivalent interactions along with good binding affinity as predicted from MM-GBSA analysis. The 2-amino-3-pyridoxime-(Arg-Asn) AChE systems subjected to MD simulations under explicit solvent systems with NPT and NVT ensemble. MD simulations uncovered dynamic behavior of 2-amino-3-pyridoxime-(Arg-Asn) and exposed its mobile nature and competence to form strong long range-order contacts towards active site residues to approach inhibited serine residue and facilitated via large contribution from hydrogen bonding and water bridges along with slow and large movements of adjacent important residues. In an effort to evaluate the complete potential surface profile, 2-amino-3-pyridoxime induced reactivation pathway of sarin–serine adduct has been investigated by the DFT approach at the vacuum MO6/6–311G (d, p) level along with the Poisson-Boltzmann solvation model and found to be of relatively low energy barrier. The pKa evaluation has revealed the major deprotonated 2-amino-3-pyridoixime species having pKa of 6.47 and hence making 2-amino-3-pyridoxime-(Arg-Asn) potential anticholinesterase and reactivator for AChE under the physiological pH.

Design, synthesis and preliminary evaluation of a novel SPECT DTPA-bis-triazaspirodecanone conjugate for D2 receptor imaging

On the basis of pharmacological behaviour, dopamine receptors are divided into D1 and D2 subtype, which are primarily responsible for several neurophysiological anomalies. Assessment and validation with SPECT based conjugates provides a promising and cost effective insight to detect molecular changes in such neurological diseases. Spiperone, a well known “butryophenone” based D2 receptor antagonist, has been explored to design a novel conjugate for SPECT evaluation. The molecular docking pose analysis of the designed molecule was explored with dopamine D2 receptor. The molecule showed high affinity (−51.318 kcal mol−1) due to conserved interactions with Asp114 and Phe389 of D2 receptor. DTPA with triazaspirodecanone moiety of spiperone was synthesized using bifunctional chelation approach with 88% yield and has been characterized using NMR and mass spectroscopy. The radiolabeling efficiency of 99mTc-DTPA-bis-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one) was 98%. The complex showed appreciable brain uptake in mice. Receptor binding experiments revealed a Kd of 6.26 nM with maximum localization of the conjugate in the striatum. Thus, these studies could be viewed as novel and informative, initial proof-of-concept approach to the field of 99mTc-labeled radioligand design.

Design, synthesis and relaxation studies of triazole linked gadolinium(III)–DO3A-BT-bistriazaspirodecanone as a potential MRI contrast agent

Magnetic resonance imaging (MRI) is a diagnostic and research technique widely used in clinical research. We describe here a novel and facile synthesis of a bisconjugated triazaspirodecanone moiety using ‘click chemistry’ as a key step in the synthesis of a triazole based macrocyclic MRI contrast agent. A bivalent approach has been applied to conjugate two triazole rings and triazaspirodecanone moieties across a four carbon spaced linker which is finally conjugated to DO3A to yield the desired MRI contrast agent, DO3A-bis(triazole-triazaspirodecanone), in an overall yield of 70%. All the intermediates and the final compounds have been characterized by NMR and mass spectrometry. In vitro experiments include cytotoxicity (MTT assay) and relaxivity studies. The potentiometric titration of a gadolinium loaded complex displayed strong selectivity for Gd3+ over physiological metal ions such as Zn2+ and Cu2+. IC50 values obtained from the MTT assay indicate the suitability of the synthesized conjugate as a safe diagnostic agent. The longitudinal relaxivity of DO3A-bis(triazole-triazaspirodecanone) was found to be 18.6 mM−1 s−1, which shows that the synthesized conjugate is a suitable MRI contrast agent.

Synthesis of novel AIEE active pyridopyrazines and their applications as chromogenic and fluorogenic probes for Hg2+ detection in aqueous media

A series of novel pyridopyrazine derivatives was synthesized in excellent yields. All compounds displayed weak fluorescence emission in solution but showed strong emission in the aggregated state indicating aggregation induced emission enhancement (AIEE) characteristics. Single crystal analysis of PP1 showed a highly twisted conformation with no π–π stacking interactions. The application of these pyridoyrazines as chromogenic and fluorogenic probes for the detection of Hg2+ ions is also reported. Pyridopyrazine derivatives bearing electron-withdrawing biphenyl rings (PP1 and PP2) act as excellent “turn-on” fluorescent probes while those bearing electron-donating biphenyl rings (PP3 and PP4) act as excellent “turn-off” fluorescent probes for Hg2+ ions in non-buffered aqueous media with high selectivity in the presence of competitive metal ions such as Na+, K+, Mg2+, Ca2+, Ba2+, Cr3+, Fe3+, Fe2+, Co2+, Ni2+, Cu2+, Ag+, Zn2+, Cd2+, Al3+ and Pb2+. A visual color change from colorless to yellow upon treatment with Hg2+ was also observed for all probes; thus, they could also be used for naked eye detection of Hg2+ ions. These probes displayed selective detection of Hg2+ ions in the range from 3.37 × 10−7 M to 8.17 × 10−8 M. The 1 : 1 binding stoichiometry for the complex formation between the pyridopyrazine derivative and Hg2+ was confirmed by Jobs plot and NMR studies. Binding of Hg2+ to pyridopyrazines was found to be reversible upon addition of KI and the process could be repeated several times. Additionally, filter paper strips coated with PP1 and PP2 were also used for the detection of Hg2+ ions.

Perception into hypoxia selectivity and electronic features of symmetrically substituted bisthiosemicarbazone ligands and their copper complexes: DFT and QM/MM docking

Bisthiosemicarbazone ligands and copper complexes, a promising class of molecules for imaging, have been studied by DFT/MO6 theory with NBO analysis to reveal strong delocalization. To shed light into the aspects of hypoxia selectivity of complexes was inferred from binding of copper complexes with HIF-1α by QM/MM docking. The affinity of copper complexes cross-validated by force filed analysis.