Benzimidazole Derivatives as Potential Antimicrobial and Antiulcer Agents: A Mini Review.

Here in we report the number of strategies for the synthesis of differently substituted benzimidazole derivatives. The protocols involved in the syntheses of these derivatives were one-pot or multi-component. The characterization studies of these derivatives were carried by using different spectroscopic techniques (1H NMR, 13C NMR and MS) and elemental analyses. The biological screening studies revealed that these benzimidazole derivatives show potential antibacterial as well as antifungal behavior. These benzimidazole derivatives not only depicted potential antiulcer properties but also showed moderate to good anticancer/cytotoxic behavior against different cancer cell lines.

Synthesis of steroidal imidazolidinthiones as potential apoptotic agents: Investigation by theoretical and experimental studies.

New steroidal imidazolidinthione derivatives (4-6) were synthesized from steroidal thiosemicarbazones and dichloroethane. The synthesized compounds were characterized using spectral data analysis. Theoretical DFT involving B3LYP/6-31G∗∗ level of theory was employed to gain insights into the molecular structure of the target compounds. MEPS and FMO analysis were carried out. HOMO-LUMO energy gap was determined which helped to evaluate various global descriptors like hardness, chemical potential, electronegativity, nucleophilicity and electrophilicity index, etc. The calculated properties established that the synthesized products are more or less similar in their reactivity behaviour. To explore their biological potential, interaction studies of compounds (4-6) with DNA were carried out using various biophysical techniques. The compounds bind DNA preferentially through electrostatic and hydrophobic interactions with Kb of 3.21 × 103 M-1, 2.79 × 103 M-1 and 2.26 × 103 M-1, respectively indicating the higher binding affinity of compound 4 towards DNA. Gel electrophoresis of compound 4 demonstrated strong interaction during the concentration dependent cleavage activity with pBR322 DNA. It was observed that these steroidal imidazolidinthiones are minor groove binders of DNA which was validated using molecular docking studies. An in vitro cytotoxicity screening using MTT assay revealed that the compounds (4-6) exhibit potential toxicity against different human cancer cells. Highest antiproliferative effect was observed on HeLa cells by compound 4. The results suggested that compounds 4-6 cause apoptotic cell death by cleaving apoptotic protein caspase-3 and suppress anti-apoptotic protein Bcl-2 in HeLa cancer cells.

DNA binding, artificial nuclease activity and cytotoxic studies of newly synthesized steroidal pyrimidines.

The new steroidal pyrimidine derivatives (4-6) were synthesized by the reaction of steroidal thiosemicarbazones with (2-methyl) diethyl malonate in absolute ethanol. After characterization by spectral and analytical data, the DNA interaction studies of compounds (4-6) were carried out by UV-vis, fluorescence spectroscopy, hydrodynamic measurements, molecular docking and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.31×103M-1, 1.93×103M-1 and 2.05×103M-1, respectively indicating the higher binding affinity of compound 4 towards DNA. Gel electrophoresis demonstrated that compound 4 showed a strong interaction during the concentration dependent cleavage activity with pBR322 DNA. The molecular docking study suggested the intercalation of steroidal pyrimidine moiety in the minor groove of DNA. During in vitro cytotoxicity, compounds (4-6) revealed potential toxicity against the different human cancer cells (MTT assay). During DAPI staining, the nuclear fragmentations on cells occurred after treatment with compounds 4 and 5. Western blotting analysis clearly indicates that compound 4 causes apoptosis in MCF-7 cancer cells. The results revealed that compound 4 has better prospectus to act as a cancer chemotherapeutic candidate, which warrants further in vivo anticancer investigations.

Spectroscopic, Viscositic, DNA Binding and Cytotoxic Studies of Newly Synthesized Steroidal Imidazolidines.

A series of new steroidal imidazolidine derivatives (4-6) were synthesized after reacting steroidal thiosemicarbazones with chloro ethylacetate in absolute ethanol. After characterization by spectral and analytical data, the interaction studies of compounds (4-6) with DNA were carried out by UV-vis, fluorescence spectroscopy, hydrodynamic measurements, molecular docking and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.63 × 10(3) M(-1), 1.81 × 10(3) M(-1) and 2.06 × 10(3) M(-1), respectively indicating the higher binding affinity of compound 4 towards DNA. Gel electrophoresis demonstrated that compound 4 showed strong interaction during the concentration dependent cleavage activity with pBR322 DNA. The molecular docking study suggested the intercalation of imidazolidine moiety of steroid derivative in minor groove of DNA. During in vitro cytotoxicity, compounds (4-6) revealed potential toxicity against the different human cancer cells (MTT assay). The uptake of compound 4 by MCF-7 and HeLa cells was studied by confocal microscopy which determined cell shrinkage and hence leading to the apoptosis. The results revealed that compound 4 has better prospectus to act as cancer chemotherapeutic candidate which warrants further in vivo anticancer investigations.

Synthesis of new steroidal imidazo [1,2-a] pyridines: DNA binding studies, cleavage activity and in vitro cytotoxicity.

A one-pot strategy for the catalytic synthesis of series of new 5α-cholestan-6-spiro-5'-phenylamino-2H-imidazo [1',2'-a] pyridines (4-14) has been investigated. The synthesized products were obtained in good yields (85-90%) and the protocol uses Multi-component Reaction (MCR) involving steroidal ketones, 2-aminopyridines, isocyanides and propylphosphonic anhydride (®T3P) as a catalyst. After characterization by spectral and analytical data, the interaction studies of compounds (4-6) with DNA were studied by UV-vis, fluorescence spectroscopy, gel electrophoresis and molecular docking. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.35×10(4), 3.71×10(4) and 3.24×10(4) M(-1), respectively, indicating the higher binding affinity of compound 5 towards DNA. Gel electrophoresis showed the concentration dependent cleavage activity of compounds 4-6 with DNA. Molecular docking studies suggested that compounds bind through minor groove to DNA. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay depicted promising anti-proliferative activity of compound 4-9 against different given cancer cells. In Western blotting, the expressions of relevant apoptotic markers depicted an apoptosis by steroidal imidazopyridines in A549 cells. Annexin V-FITC/PI staining data indicated that compounds could effectively induce apoptosis in A549 cells in a dose-dependent manner. FACS analysis shows that the compound 6 bring about cell cycle arrest at 2.62 µM concentration.

DNA Interaction Studies and In Vitro Cytotoxicity of Newly Synthesized Steroidal Imidazolidinones.

New steroidal imidazolidinone derivatives (7-9) were synthesized after reacting steroidal thiosemicarbazones with oxalyl chloride in absolute ethanol. After characterization by spectral and analytical data, the interaction studies of compounds (7-9) with DNA were carried out by UV-vis, fluorescence spectroscopy, circular dichroism, molecular docking and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.31 × 10(4) M(-1), 2.57 × 10(4) M(-1) and 2.16 × 10(4) M(-1), respectively indicating the higher binding affinity of compound 8 towards DNA. Gel electrophoresis demonstrated that the compounds 7-9 show strong interaction during the cleavage activity with pBR322 DNA. The docking study suggested the intercalation of imidazolidinone moiety of steroid derivative in minor groove of DNA. During in vitro cytotoxicity, compounds 7-9 revealed potential toxicity against the different human cancer cells (MTT assay). Apoptotic degradation of DNA in presence of compounds 7-9 was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay). FACS analysis shows that the compound 8 bring about cell cycle arrest at 7 µM concentration.

Steroidal dihydrocarbothioic acid amido pyrazoles: synthesis, characterization, cytotoxicity and genotoxicity studies.

A new series of steroidal dihydrocarbothioic acid amido pyrazole analogues were synthesized, and after characterization, evaluation for cytotoxicity, comet assay and western blotting was carried out. The synthesis of these analogues is convenient and involves two steps, i.e. aldol condensation as first step followed by nucleophilic addition of thiosemicarbazide across α, ß-unsaturated carbonyl as a later step. Quantitative yields of more than 80 % are obtained in both the steps. After characterization by IR, (1)H NMR, (13)C NMR, MS and analytical data, all the compounds of both series were tested for cytotoxic activity against a panel of different human cancer cell lines by MTT assay, during which compound 3e, 3f, 4e, 4f and 4h are very potent especially against HepG2 and MCF-7 cancer cell lines. Cell cycle analysis depicted the cell death in S-phase while as annexin V-FITC/PI analysis showed that compounds effectively induce apoptosis. Apoptotic degradation of DNA of MCF-7 cells in the presence of different steroidal derivatives was analysed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay). In western blotting analysis, the relative expressions of relevant apoptotic markers depicted an apoptosis by steroidal dihydropyrazole in MCF-7 cancer cells.

In vitro cytotoxcity and interaction of new steroidal oxadiazinanones with calf thymus DNA using molecular docking, gel electrophoresis and spectroscopic techniques.

Herein we report synthesis of new steroidal oxadiazinanones from steroidal ketones. After characterization by spectral and analytical data, the interaction studies of compounds (4-6) with DNA were carried out by UV-vis, fluorescence spectroscopy and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 1.8×10(4) M(-1), 2.2×10(4) M(-1) and 2.6×10(4) M(-1), respectively, indicating the higher binding affinity of compound 6 towards DNA. Gel electrophoresis showed the concentration dependent cleavage activity of compound 6 alone or in presence of Cu (II) causes the nicking of supercoiled pBR322 and it seems to follow the mechanistic pathway involving generation of hydroxyl radicals that are responsible for initiating DNA strand scission. Molecular simulations suggest that compounds binds through minor groove of DNA. MTT assay depicted promising anticancer activity of compound 5 and 6 particularly against HL-60 and MCF-7. The apoptotic degradation of DNA was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay). The results revealed that compound 6 has better prospectus to act as cancer chemotherapeutic candidate which warrants further in vivo anticancer investigations.

Physicochemical properties of nanomaterials: implication in associated toxic manifestations.

Nanotechnology has emerged as one of the leading fields of the science having tremendous application in diverse disciplines. As nanomaterials are increasingly becoming part of everyday consumer products, it is imperative to assess their impact on living organisms and on the environment. Physicochemical characteristics of nanoparticles and engineered nanomaterials including size, shape, chemical composition, physiochemical stability, crystal structure, surface area, surface energy, and surface roughness generally influence the toxic manifestations of these nanomaterials. This compels the research fraternity to evaluate the role of these properties in determining associated toxicity issues. Reckoning with this fact, in this paper, issues pertaining to the physicochemical properties of nanomaterials as it relates to the toxicity of the nanomaterials are discussed.

Synthesis, molecular docking and biological evaluation of new steroidal 4H-pyrans.

A series of new steroidal 4H-pyrans (4-6) have been synthesized from steroidal α, ß-unsaturated ketones (1-3). The products (4-6) were characterized by IR, (1)H NMR, (13)C NMR, MS and analytical data. The interaction studies of compounds (4-6) with DNA were carried out by employing gel electrophoresis, UV-vis and fluorescence spectroscopy. The gel electrophoresis pattern revealed that compounds (4-6) bind to DNA and also demonstrated that the compound 6 alone or in presence of Cu (II) causes the nicking of supercoiled pBR322. The compounds 4 and 5 bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb values found to be 5.3×10(3) and 3.7×10(3) M(-1), respectively, indicating the higher binding affinity of compound 4 towards DNA. The docking study suggested the intercalation of compounds in between the nucleotide base pairs. The cytotoxicity and genotoxicity of the newly synthesized compounds were checked by MTT and comet assay, respectively during which compound 6 showed potential behaviour.

Synthesis and biological studies of steroidal pyran based derivatives.

Steroid based cancer chemotherapeutic agents of the type 2'-amino-3'-cyanocholest-6-eno[5,7-de]4H-pyrans (1c-3c) have been synthesized and characterized by the various spectroscopic and analytical techniques. The DNA binding studies of compounds (1c-3c) with CT DNA were carried out by UV-vis and fluorescence spectroscopy and gel electrophoresis. The compounds (1c-3c) bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb values found to be 5.4 × 10(3), 2.3 × 10(3)M(-1) and 1.97 × 10(3)M(-1), respectively indicating the higher binding affinity of compound (1c) towards DNA. The molecular docking study suggested that the electrostatic interaction of compounds (1c-3c) in between the nucleotide base pairs is due to the presence of pyran moiety in steroid molecule. All the compounds (1c-3c) cleave supercoiled pBR322 DNA via hydrolytic pathway, as validated by T4 DNA ligase assay. The compounds (1c-3c) were screened for in vitro cytotoxicity against the cancer and non-cancer cells SW480, A549, HepG2, HeLa, MCF-7, HL-60, DU-145, NL-20, HPC and HPLF by MTT assay. The compounds (1c-3c) were tested for genotoxicity (comet assay) involving apoptotic degradation of DNA and was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining. The results revealed that compound (1c) has better prospectus to act as cancer chemotherapeutic candidate which warrants further in vivo anticancer investigations.