Ashish Radadiya

Diversity oriented design of various hydrazides and their in vitro evaluation against Mycobacterium tuberculosis H37Rv strains

Control and prevention of tuberculosis is a major challenge, as one-third of the worlds population is infected with Mycobacterium tuberculosis. The resurgence of tuberculosis and the emergence of multidrug-resistance strains of mycobacteria, necessitate the search for new class of antimycobacterial agents. As a part of investigation of new antitubercular agents in this laboratory, we describe the syntheses of various hydrazides of comarins, quinolones and pyrroles and screening against M. tuberculosis (Mtb) H37(Rv) by using rifampin as a standard drug. Among the designed molecules, the most prominent compounds 2a-g, 4a and 9a showed >90% GI at MIC<6.25 μg/mL. Finally, these studies suggests that compounds 2a-g, 4a and 9a may serve as promising lead scaffolds for further generation of new anti-TB agents.

Bioactive benzofuran derivatives: An insight on lead developments, radioligands and advances of the last decade.

Benzofuran core is a highly versatile, presents in many important natural products and natural drugs. Many benzofuran containing synthetic drugs and clinical candidates have been derived from natural products. The present review will provide an insight on lead design-developments of the decade, clinical candidates and PET tracer radio-ligands containing benzofuran core along with brief target biology. Brief of the all approved drugs containing benzofuran core also have been enclosed. Main therapeutic areas covered are Cancer, Neurological disorders including anti-psychotic agent and diabetes.

Synthesis and in vitro anti-HIV activity of N-1,3-benzo[d]thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl)acetamide derivatives using MTT method.

A series of novel N-1,3-benzo[d]thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl)acetamide derivatives has been synthesized. All the newly synthesized compounds were evaluated for their anti-HIV activity using MTT method. Most of these compounds showed moderate to potent activity against wild-type HIV-1 with an EC(50) ranging from >7 EC(50) [μg/ml] to <100 EC(50) [μg/ml]. Among them, N-1,3-benzo[d]thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl)acetamide 6v was identified as the most promising compound (EC(50)=<7 μg/ml). Among all the compounds, three compounds 6m, 6v and 6u have been exhibits potent anti-HIV activity against MT-4 cells.

Synthesis of some novel benzofuran-2-yl(4,5-dihyro-3,5-substituted diphenylpyrazol-1-yl) methanones and studies on the antiproliferative effects and reversal of multidrug resistance of human MDR1-gene transfected mouse lymphoma cells in vitro.

A new series of benzofuran-2-yl(4,5-diydro-3,5-substituted diphenylpyrazol-1-yl) methanone derivatives 8a-x by the reaction of the benzofuran-2-carbohydrazides 7 with various chalcone derivatives 3a-x using microwave irradiation has been described. The effect of synthesized compounds 8a-v was studied against human cancer cell lines for their antiproliferative activity and reversal of multidrug resistance on human MDR1-gene transfected mouse lymphoma cells. Among the 24 compounds, the 8c and 8h showed good antiproliferative activity 8b, 8f and 8k were exhibited good MDR reversal activity. The main significance of the process is easy workup process, short reaction time and high yield of the new compounds for biological interest. However, the studies on genetically modified multidrug resistant cancer cells are costly and time consuming.

Synthesis and biological evaluation of 4-styrylcoumarin derivatives as inhibitors of TNF-α and IL-6 with anti-tubercular activity

A series of 4-styrylcoumarin have been synthesized by Knoevenagel condensation between substituted 4-methylcoumarin-3-carbonitrile and different heterocyclic or aromatic aldehydes. 4-Methylcoumarin-3-carbonitrile has been synthesized by the base catalyzed reaction between substituted 2-hydroxyacetophenone and ethyl cyanoacetate. The structures of the newly synthesized compounds were confirmed by (1)H NMR, IR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory activity (against TNF-α and IL-6) and anti-tubercular activity. Compounds 6a, 6h and 6j exhibited promising activity against IL-6 with 72-87% inhibition and compound 6v showed potent activity against TNF-α with 73% inhibition at 10 μM concentration. Whereas compounds 6n, 6o, 6r and 6u showed very good anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain at <6.25 μM.

Synthesis and 3D-QSAR study of 1,4-dihydropyridine derivatives as MDR cancer reverters

A series of symmetrical and unsymmetrical 1,4-dihydropyridines were synthesized by a rapid, single pot microwave irradiation (MWI) based protocol along with conventional approach and characterized by NMR, IR and mass spectroscopic techniques. The compounds were evaluated for their tumor cell cytotoxicity in HL-60 tumor cells. A 3D-QSAR study using CoMFA and CoMSIA was carried out to decipher the factors governing MDR reversing ability in cancer. The resulting contour maps derived by the best 3D-QSAR models provide a good insight into the molecular features relevant to the biological activity in this series of analogs. 3D contour maps as a result of 3D-QSAR were utilized to identify some novel features that can be incorporated into the 1,4-dihydropyridine framework to enhance the activity.

Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics.

Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of −10.3983 (kcal mol−1). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity.

Identification of Novel GSK1070916 Analogs as Potential Aurora B Inhibitors: Insights from Molecular Dynamics and MM/GBSA Based Rescoring

The discovery of promising targets for anticancer drug development has emerged with many potential enzymes. Among these, the aurora family of kinases has become a very lucrative target with some potential inhibitors in its arsenal. Recent findings show that targeting aurora B itself is sufficient to exhibit anticancer activity. When compared with other anticancer targets, aurora B has a very limited number of specific inhibitors. Recently GSK1070916 and reversine were discovered as promising new aurora B inhibitors. Amongst these GSK1070916 emerged as the most potent molecule targeting aurora B. Taking the scaffold of GSK1070916 as a reference, new molecules were designed by isosteric/bioisosteric and fragment based modifications. Furthermore, an accurate cross-platform docking, MM/GBSA based rescoring, molecular dynamics simulation were carried out to compare the binding conformation and affinities of the designed molecules with the references. Top two designed molecules showed better docking score and a better binding free energy profile as compared to reversine and GSK1070916 with the best ligand retaining conserved hydrogen bond and salt bridge interactions with Ala173, Ala233 and Lys122. The binding mode of top two designed ligands is relatively similar to that of reversine and GSK1070916. Molecular dynamics simulations proved that the identified hits are rather stable in the enzyme active site pocket, which further confirms the potential of the designed ligands as a specific target for aurora B. We believe that findings of this study will provide medicinal chemists with potential markers towards the design of potent anticancer drug design targeting aurora B and a broad range of aurora kinases.

Efficient and Rapid Synthesis of Highly Functionalized Novel Symmetric 1,4-Dihydropyridines Using Glacial Acetic Acid as Solvent

Abstract A new series of 1,4-dihydropyridines bearing a pyrazole moiety in the 4-position were synthesized by a variation of the classical Hantzsch synthesis. The reaction of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde 4a–n with 3-amino crotononitrile in the presence of glacial acetic acid afforded novel 3,5-dicyano-2,6-dimethyl 1,4-dihydropyridines 5a–n. The procedure has short reaction time (15–20 min), easy workup, and good yield of product. The structures of all synthesized compounds were well characterized by mass, infrared, 1H and 13C NMR, and elemental analysis. GRAPHICAL ABSTRACT

Insights into the structural perturbations of spliced variants of CD44: a modeling and simulation approach

Transient interactions between cancer stem cells and components of the tumor microenvironment initiate various signaling pathways crucial for carcinogenesis. Predominant hyaluronan (HA) receptor, CD44 is structurally and functionally one of the most variable cell surface receptors having the potential to generate a diverse repertory of CD44 isoforms by alternative splicing of variant exons and post-translational modifications. A structurally distinctive variant of CD44, CD44v10, has an inevitable role in malignant progression, invasion, and metastasis. This can be attributed to the binding of HA with CD44v10, which demonstrates a completely different behavioral pattern as compared to the other spliced variants of CD44 molecule. Absence of a comprehensively predicted crystal structure of human CD44s and CD44v10 is an impediment in understanding the resultant structural alterations caused by the binding of HA. Thus, in this study, we aim to predict the CD44s and CD44v10 structures to their closest native confirmation and study the HA binding-induced structural perturbations using homology modeling, molecular docking, and MD simulation approach. The results depicted that modeled 3D structures of CD44s and CD44v10 isoforms were found to be stable throughout MD simulations; however, a substantial decrease was observed in the binding affinity of HA with CD44v10 (−5.355 kcal/mol) as compared to CD44s. Furthermore, loss and gain of several H-bonds and hydrophobic interactions in CD44v10–HA complex during the simulation process not only elucidated the reason for decreased binding affinity for HA but also prompted toward the plausible role of HA-induced structural perturbations in occurrence and progression of carcinogenesis.