Himanshu Ojha

Quantitative structure activity relationship study of 2,4,6-trisubstituted-s-triazine derivatives as antimalarial inhibitors of Plasmodium falciparum dihydrofolate reductase.

This study presents a quantitative structure activity relationships (QSAR) study on a pool of 19 bio‐active s‐triazine compounds. Molecular descriptors, kappa {1κ}, chi {3χ}, x component of the dipole moment (μx), Coulson charge (qN) on the nitrogen atom sandwiched between the two substituted carbons of the triazine ring, and total energy (ET) obtained from AM1 calculations provide valuable information and have a significant role in the assessment of dihydrofolate reductase (DHFR) inhibitory activity of the compounds. By using the Genetic Function Approach (GFA) technique, five QSAR models have been drawn up with the help of these calculated descriptors and DHFR inhibitory activity data of the molecules. Among the obtained QSAR models presented in the study, statistically the most significant one is a four‐parameter linear equation with the Lack‐of‐Fit value 0.5624, squared correlation coefficient R 2 value of 0.7697, and the squared cross‐validated correlation coefficient RCV2 value of 0.6469. The results are discussed in light of the main factors that influence the DHFR inhibitory activity.

Design, synthesis, and in vitro antiproliferative activity of benzimidazole analogues for radiopharmaceutical efficacy.

The synthesis of eight ligands by using 2-amino benzimidazole with different mono/bis aldehydes is described herein. The final products were characterized by spectral techniques such as FT-IR, (1)H NMR, and EI-Mass. The structure-activity relationships of the benzimidazole derivatives are also reported. Studies on the complexation of the ligands with (99m)Tc were optimized by using stannous tartrate as reducing agent under various reaction conditions. The radiochemical stability was >or=95% for all the complexes, and they were to be stable for 12-14 hours in serum. Most of the ligands showed fast blood clearance. Biodistribution studies of the (99m)Tc complexes of these ligands showed no significant uptake in the brain or in the heart, and the clearance was mainly through the hepatobiliary system. Among the eight compounds evaluated for their antiproliferative activity in vitro, L(8) produced good activity against the cancer cell lines A549 and PC-3.

Quantitative Structure–Property Relationship (Correlation Analysis) of Phosphonic Acid-Based Chelates in Design of MRI Contrast Agent

Nuclear magnetic resonance imaging is a very useful tool in modern medical diagnostics, especially when gadolinium (III)‐based contrast agents are administered to the patient with the aim of increasing the image contrast between normal and diseased tissues. With the use of soft modelling techniques such as quantitative structure–activity relationship/quantitative structure–property relationship after a suitable description of their molecular structure, we have studied a series of phosphonic acid for designing new MRI contrast agent. Quantitative structure–property relationship studies with multiple linear regression analysis were applied to find correlation between different calculated molecular descriptors of the phosphonic acid‐based chelating agent and their stability constants. The final quantitative structure–property relationship mathematical models were found as – quantitative structure–property relationship Model for phosphonic acid series (Model 1) − log KML = {5.00243(±0.7102)}− MR {0.0263(±0.540)}n = 12 l r l = 0.942 s = 0.183 F = 99.165 quantitative structure–property relationship Model for phosphonic acid series (Model 2) − log KML = {5.06280(±0.3418)}− MR {0.0252(± .198)}n = 12 l r l = 0.956 s = 0.186 F = 99.256.

SAR of Cu (II) Thiosemicarbazone Complexes as Hypoxic Imaging Agents: MM3 Analysis and Prediction of Biologic Properties

Copper(II) bis(thiosemicarbazone) are very useful for blood flow and hypoxic imaging. The aim of this study was to identify structure-activity relationships (SARs) within a series of analogues with different substitution patterns in the ligands, in order to design improved hypoxia imaging agents and elucidate hypoxia selectivity mechanisms. Genetic algorithms (GAs) were used to develop specific copper metal-ligand force field parameters for the MM3 force-field calculations. These new parameters produced results in good agreement with experiment and previously reported copper metal-ligand parameters. A successful quantitative SAR (QSAR) for predicting the several classes of Cu(II)-chelating ligands was built using a training set of 21 Cu(II) complexes. The QSAR exhibited a correlation between the predicted and experimental test set. The QSAR preformed with great accuracy; r(2) = 0.95 and q(2) = 0.90 utilizing a leave-one-out cross-validation with multiple linear regression analysis to find correlation between different calculated molecular descriptors of these complexes. The final QSAR mathematical models were found as the following: Log P = {3.01698 (+/-0.0590)} - LUMO {0.1248 (+/-0.068)} + MR {0.3219 (+/-0.086)} n = 21 |r| = 0.972 s = 0.188 F = 98.102 The resulting models could act as an efficient strategy for estimating the hypoxic conditions through imaging and provide some insights into the structural features related to the biological activity of these compounds.

Luminescence, circular dichroism and in silico studies of binding interaction of synthesized naphthylchalcone derivatives with bovine serum albumin

Chalcones possess various biological properties, for example, antimicrobial, anti-inflammatory, analgesic, antimalarial, anticancer, antiprotozoal and antitubercular activity. In this study, naphthylchalcone derivatives were synthesized and characterized using 1 H NMR 13 C NMR, Fourier transform infrared and mass techniques. Yields for all derivatives were found to be >90%. Protein-drug interactions influence the absorption, distribution, metabolism and excretion (ADME) properties of a drug. Therefore, to establish whether the synthesized naphthylchalcone derivatives can be used as drugs, their binding interaction toward a serum protein (bovine serum albumin) was investigated using fluorescence, circular dichroism and molecular docking techniques under physiological conditions. Fluorescence quenching of the protein in the presence of naphthylchalcone derivatives, and other derived parameters such as association constants, number of binding sites and static quenching involving confirmed non-covalent binding interactions in the protein-ligand complex were observed. Circular dichroism clearly showed changes in the secondary structure of the protein in the presence of naphthylchalcones, indicating binding between the derivatives and the serum protein. Molecular modelling further confirmed the binding mode of naphthylchalcone derivatives in bovine serum albumin. A site-specific molecular docking study of naphthylchalcone derivatives with serum albumin showed that binding took place primarily in the aromatic low helix and then in subdomain II. The dominance of hydrophobic, hydrophilic and hydrogen bonding was clearly visible and was responsible for stabilization of the complex.

Ex-vivo complexation, skin permeation, interaction and cytodermal toxicity studies of p-tertbutylcalix[4]arene nanoemulsion for radiation decontamination

Aims: p‐tertbutylcalix[4]arene loaded nanoemulsion has been designed, characterized and evaluated for skin decontamination of radionuclides of interest in nuclear and radiological emergencies. Further, nanoemulsion was evaluated for Ex‐vivo complexation, skin permeation, interaction and cytodermal toxicity. Materials and methods: Ex‐vivo skin complexation studies were conducted using High‐resolution sector field inductively coupled plasma mass spectroscopy (HR‐SF‐ICPMS). Skin studies at dermal and cyto‐dermal level have been carried out using techniques such as florescence microscopy, Differential scanning calorimetry (DSC), Flow cytometry, Confocal microscopy, Prestoblue and Comet assay. Key findings: HR‐SF‐ICPMS study confirmed > 95% complexation of surrogate nuclides of thallium and Iodine applied on excised rat skin mounted over Franz diffusion cell. Temporal analysis of aliquots obtained from Franz diffusion cell using UV–Vis absorption spectroscopy indicated that only 3.37% of formulation permeates through the skin. Skin penetration study of rhodamine 123 nanoemulsion carried out using florescence microscopy confirmed that formulation remains localised in epidermis of rat skin. DSC data confirmed skin compatibility of nanoemulsion, as no lipid extraction was observed from skin. In‐vitro cell viability and cellular uptake assays performed on human skin fibroblasts prove no cellular uptake and cytotoxic effects. Comet assay, cell cycle arrest, and apoptosis‐inducing mechanistic studies prove that prepared nanoemulsion is safe at cellular level. Significance: Taken together, data indicate that p‐tertbutylcalix[4]arene nanoemulsion is both effective and safe formulation to use on skin for radio‐decontamination. Graphical abstract Figure. No caption available.

Design, synthesis and biological evaluation of methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate: TSPO ligand for SPECT

The translator protein (TSPO, 18 kDa), a transmembrane mitochondrial protein, has been explored as an important biomarker by researchers because of its involvement in inflammation, immune modulation and cell proliferation. Recently, our group has explored a modified benzoxazolone derivative for diagnostic applications that has overcome few problems of first and second generation TSPO PET ligands. In this study, a new skeleton acetamidobenzoxazolone–indole, a conjugation of two TSPO pharmacophoric moieties benzoxazolone and indole, has been designed, synthesized and evaluated for TSPO targeting for SPECT. The methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate (MBIP) ligand was designed on the basis of pharmacophore modeling done on benzoxazolone based TSPO ligands which was then validated computationally for TSPO binding through docking studies (PDB ID: 4RYO, 4RYQ, and 4UC1) which showed a comparable Glide Gscore as compared to known ligands like PK11195, PBR28, and FGIN-127. MBIP was synthesized by amidation reaction of 2-(5-bromo-benzoxazolone)acetic acid with tryptophan methyl ester hydrochloride (yield 62%). The compound was synthesized and characterized using spectroscopic techniques like 1H-NMR, 13C-NMR, and mass spectroscopy. Purification was carried out by column chromatography and analytical HPLC (purity > 97%). The purified compound was labelled with 99mTc (radiochemical yield > 96%). The radiolabelled compound showed >94% stability in solution and >91% stability in serum after 24 h indicating the stable nature of the radio complex. A biodistribution study on BALB/c mice showed uptake of 99mTc-MBIP in TSPO rich organs and appropriate pharmacokinetics of excretion and release for a SPECT agent. Further evaluation of the 99mTc-MBIP may prove it as a potential candidate for TSPO targeting using SPECT.

Nanotechnology-based drug delivery systems: Challenges and opportunities

Abstract There is a need of a carrier that can deliver drugs to the targeted cells and organs, where it can prolong and localize its effect, interacting with the diseased part of the organ specifically to obtain the maximum therapeutic efficiency. There are various methods aimed at the packaging of drug molecules in nanoparticles that can specifically deliver the drug to the pathological area. These nanoparticles are designed in a way that they target the affected region of the particular organ without interacting with the healthy part. Nanoparticles have the ability to cross the cell membrane easily so that it is targeted to the diseased tissue, which in turn decreases the rate of drug doses that have a more uniform effect, reducing the side effect of drug. However, there are various ways to synthesize nanoparticles for packaging of drug compounds and they require a systematic review to analyze their operational efficiency, safety, up-scaling and costs. Therefore, this chapter undertakes a detailed investigation of various factors that influence nanoparticle-based drug delivery systems.