Design, synthesis, docking studies and biological screening of 2-thiazolyl substituted -2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines as potent HIV-1 reverse transcriptase inhibitors.

1,3-oxazine nucleus and thiazolyl group features prominently in many biologically important natural products as well as bioactive molecules. A series of novel 2-thiazolyl substituted-2,3-dihydro-1H-naphtho [1,2-e][1,3]oxazine derivatives were designed and synthesized based on their structure-activity relationships (SARs) from 2-naphthol, substituted thiazolyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were first evaluated for their inhibitory effect on HIV-1 Reverse Transcriptase (RT) enzyme activity. Out of 14 compounds, 4 showed potent inhibition of HIV-1 RT activity at significantly low concentration. Docking studies of these molecules revealed their high affinity binding to several amino acids of HIV-1 RT which are less sensitive to point mutations. Furthermore, anti-HIV activity of these molecules was analysed in a CD4+ T cell-line, which indicates that Therapeutic Index (TI) of some of these compounds is better than Zidovudine and Efavirenz, known HIV-1 RT inhibitors. Taken together, our studies report for the first time some novel naphthoxazine derivatives with significant TI, which is through inhibition of HIV-1 RT activity.

Synthesis and antimycobacterial screening of new thiazolyl-oxazole derivatives.

In the present study a series of 4-methyl-2-aryl-5-(2-aryl/benzyl thiazol-4-yl) oxazole (4a-v) have been synthesized and evaluated for their preliminary antitubercular, antimicrobial and cytotoxicity activity. Among all the synthesized compounds, 4v reported comparable activity against dormant M. tuberculosis H37Ra and M. bovis BCG strains with respect to standard drug rifampicin. The active compounds from the antitubercular study were further tested for anti-proliferative activity against HeLa, A549 and PANC-1 cell lines using MTT assay and showed no significant cytotoxic activity at the maximum concentration evaluated. Further, the synthesized compounds were found to have potential antibacterial activities with MIC range of 2.1-26.8 µg/mL. High potency, lower cytotoxicity and promising antimycobacterial activity suggested that these compounds could serve as good leads for further optimisation and development.

Hybrids of thienopyrimidinones and thiouracils as anti-tubercular agents: SAR and docking studies.

A number of hybrid molecules containing thienopyrimidinones and thiouracil moieties were designed, synthesized and tested against Mycobacterium tuberculosis H37Ra wherein it was observed that the compounds 11-14 exhibited antitubercular activity in vitro (MIC 7.6-19.1 µg/mL, 12-35 µM) against dormant stage while the compound 15 exhibited antitubercular activity in vitro against dormant (MIC 23.4 µg/mL, 41 µM) as well as active (MIC 25.4 µg/mL, 45 µM) stage. Structural modifications of the compound 15 were carried out to study the structure-activity relationship and it was observed that the compound 18 exhibited antitubercular activity comparable to the compound 15. Cytotoxicity studies revealed that these molecules were non-toxic. The docking study of the compound 15 showed that there was binding with the active site of mycobacterial pantothenate synthetase. Further docking studies led to the synthesis of the compounds 16 and 17 and the antitubercular activity screening results showed that these compounds have significant antitubercular activity. The compounds 15-18 (MIC 11-29 µg/mL, 19-51 µM) can be used as starting points for further optimization. The synthetic strategies used in the present work have potential to prepare a large number of compounds for further refinement of structures and the present results will be very useful in the development of a new class of antimycobacterial agents.

Poly(ethylene glycol) versus dendrimer prodrug conjugates: influence of prodrug architecture in cellular uptake and transferrin mediated targeting.

Many polymer based drug delivery nanosystems are currently being explored for delivering cytotoxic agents to the tumors. However, very few strategies delineate the comparative carrier ability of nanosystems, in similar experimental settings. As a result, it remains unclear how to optimally design polymer based multicomponent prodrug systems for delivery applications. The present study is aimed to design polymeric prodrug conjugate carriers for the comparative cellular delivery ability of anticancer drug doxorubicin hydrochloride (DOX) using linear poly(ethylene glycol) (PEG), hyperbranched poly(amido amine) (PAMAM) G4 dendrimer, and PAMAM G4 dendrimer-PEG conjugate using MCF-7 cells. Furthermore, the cellular targetability and in vitro anticancer activity of DOX conjugates is evaluated using transferrin (Tf) as a targeting ligand. Interestingly, conjugation of DOX to PAMAM G4-OH dendrimer significantly influences the cytotoxicity of DOX leading to -4 fold decrease in the IC50 dose when compared to pegylated DOX. This study establishes the rational and comparative structural activity relationship of polymeric prodrug carriers for delivery of anticancer drugs. The schematic representation of design of prodrug conjugates with varied polymeric architecures is as shown below (Fig. 1).

Transferrin-mediated rapid targeting, isolation, and detection of circulating tumor cells by multifunctional magneto-dendritic nanosystem.

A multicomponent magneto-dendritic nanosystem (MDNS) is designed for rapid tumor cell targeting, isolation, and high-resolution imaging by a facile bioconjugation approach. The highly efficient and rapid-acting MDNS provides a convenient platform for simultaneous isolation and high-resolution imaging of tumor cells, potentially leading towards an early diagnosis of cancer.

Enhancing surface interactions with colon cancer cells on a transferrin-conjugated 3D nanostructured substrate.

A transferrin-conjugated PEG-Fe(3) O(4) nanostructured matrix is developed to explore cellular responses in terms of enhanced cell adhesion, specific interactions between ligands in the matrix and molecular receptors on the cell membrane, comparison of cell shapes on 2D and 3D surfaces, and effect of polymer architecture on cell adhesion. Integration of such advanced synthetic nanomaterials into a functionalized 3D matrix to control cell behavior on surfaces will have implications in nanomedicine.

PEG-conjugated highly dispersive multifunctional magnetic multi-walled carbon nanotubes for cellular imaging.

We report synthesis of a highly versatile multicomponent nanosystem by covalently decorating the surface of multiwalled carbon nanotubes (CNTs) by magnetite nanoparticles (Fe(3)O(4)), poly(ethylene glycol) (PEG), and fluorophore fluorescein isothiocyanate (FITC). The resulting Fe(3)O(4)-PEG-FITC-CNT nanosystem demonstrates high dispersion ability in an aqueous medium, magnetic responsiveness, and fluorescent capacity. Transmission electron microscopy images revealed that Fe(3)O(4) nanoparticles were well anchored onto the surfaces of the CNT. In vitro time kinetic experiments using confocal microscopy demonstrated a higher uptake of the Fe(3)O(4)-PEG-FITC-CNT nanosystem localized at the perinuclear region of MCF7 cells compared to the free FITC. In addition, the CNT nanosystem demonstrated no evidence of toxicity on cell growth. Surface conjugation of multicomponents, combined with in vitro non-toxicity, enhanced cellular uptake for FITC and site specific targeting ability makes this fluorescent Fe(3)O(4)-PEG-FITC-CNT nanosystem an ideal candidate for bioimaging, both in vitro and in vivo.