Discovery of novel dihydronaphthalene-imidazole ligands as potential inhibitors of Staphylococcus aureus multidrug resistant NorA efflux pump: A combination of experimental and in silico molecular docking studies.

Overexpression of the efflux pump is a predominant mechanism by which bacteria show antimicrobial resistance (AMR) and leads to the global emergence of multidrug resistance (MDR). In this work, the inhibitory potential of library of dihydronapthyl scaffold-based imidazole derivatives having structural resemblances with some known efflux pump inhibitors (EPI) were designed, synthesized and evaluated against efflux pump inhibitor against overexpressing bacterial strains to study the synergistic effect of compounds and antibiotics. Out of 15 compounds, four compounds (Dz-1, Dz-3, Dz-7, and Dz-8) were found to be highly active. DZ-3 modulated the MIC of ciprofloxacin, erythromycin, and tetracycline by 128-fold each against 1199B, XU212 and RN4220 strains of S. aureus respectively. DZ-3 also potentiated tetracycline by 64-fold in E. coli AG100 strain. DZ-7 modulated the MIC of both tetracycline and erythromycin 128-fold each in S. aureus XU212 and S. aureus RN4220 strains. DZ-1 and DZ-8 showed the moderate reduction in MIC of tetracycline in E. coli AG100 only by 16-fold and 8-fold, respectively. DZ-3 was found to be the potential inhibitor of NorA as determined by ethidium bromide efflux inhibition and accumulation studies employing NorA overexpressing strain SA-1199B. DZ-3 displayed EPI activity at non-cytotoxic concentration to human cells and did not possess any antibacterial activity. Furthermore, molecular docking studies of DZ-3 was carried out in order to understand the possible binding sites of DZ-3 with the active site of the protein. These studies indicate that dihydronaphthalene scaffolds could serve as valuable cores for the development of promising EPIs.

Nanoparticles Encapsulated γ-Oryzanol as a Natural Prodrug of Ferulic Acid for the Treatment of Oxidative Liver Damage.

Antioxidants are promising therapeutics for treating oxidative stress-mediated liver diseases. Previously, we studied a potent natural antioxidant, ferulic acid, and developed a liposomal formulation of ferulic acid (ferulic-lipo) to improve its solubility. Ferulic-lipo significantly attenuated oxidative damage in the liver by inhibiting reactive oxygenase species (ROS). However, antioxidative liposomes must be less reactive with ROS prior to reaching the target sites to effectively neutralize existing ROS. But ferulic-lipo tends to be oxidized before reaching the liver. Besides, γ-oryzanol has been reported to decompose into ferulic acid in vivo; accordingly, we hypothesized that γ-oryzanol could be employed as a natural prodrug of ferulic acid to improve stability and antioxidative effectiveness. Therefore, in this study, we prepared a liposomal formulation of γ-oryzanol (γ-ory-lipo) and investigated its therapeutic effects in a CCl4-induced rat model of liver injury. We found that γ-ory-lipo has a higher chemical stability than does free γ-oryzanol. Although the antioxidative effect of γ-ory-lipo was lower than that of ferulic-lipo, pretreatment of the HepG2 cells with γ-ory-lipo improved the viability of CCl4-treated cells to a similar level as treatment with ferulic-lipo. γ-Oryzanol was shown to be converted into ferulic acid in vitro and in vivo. Furthermore, intravenous administration of γ-ory-lipo exhibited a similar effectiveness as ferulic-lipo against CCl4-induced hepatotoxicity, which should be the due to the conversion of γ-oryzanol into ferulic acid. These findings demonstrated that γ-ory-lipo could be a good natural prodrug of ferulic acid for eradicating its stability problem.

Protective effects of liposomes encapsulating ferulic acid against CCl4-induced oxidative liver damage in vivo rat model.

Antioxidants are useful for the treatment of oxidative stress mediated liver damage. A naturally occurring antioxidant γ-oryzanol is rapidly hydrolyzed to its active hydrophobic metabolite, ferulic acid, inside the body. Limitations associated with the hydrophobicity of ferulic acid can be overcome by encapsulating in a liposomal formulation. As intravenously administered nanoparticles (including liposomes) can effectively reach the liver, such systems may be suitable drug delivery carriers to treat liver injury. In this study, we prepared a liposomal formulation of ferulic acid (ferulic-lipo) and examined its effects on liver damage induced by CCl4. Ferulic-lipo were ~100 nm in size and drug encapsulation efficiency was about 92%. Ferulic-lipo showed potent scavenging efficacy against hydroxyl radical compared to α-tocopherol liposomes. Ferulic-lipo significantly prevented CCl4-mediated cytotoxicity in human hepatocarcinoma cells. Furthermore, intravenous administration of ferulic-lipo significantly reduced alanine aminotransferase and aspartate amino transferase levels in a rat model of liver injury. CCl4-mediated reactive oxygen species generation in liver was also reduced by intravenous administration of ferulic-lipo. Hepatoprotective effects of ferulic-lipo were demonstrated by histological observation of CCl4-induced liver tissue damage. Therefore, ferulic-lipo exhibit potent antioxidative capacity and were suggested to be an effective formulation for prevention of oxidative damage of liver tissue.

Platanic Acid-Aryl Enones as Potential Anticancer Compounds: Synthesis and Biological Profiling against Breast, Prostate and Lung Cancer Cell Lines.

A series of rationally designed platanic acid-based compounds derived from naturally occurring betulinic acid were synthesized through a sequence of Lemieux-Johnson oxidation and Aldol condensation reaction. All the compounds were screened for cytotoxicity against a panel of human cancer and normal cell lines using MTT assay. From the biological data, it was observed that some of these semi-synthetic congeners exhibited potent biological profiles compared to platanic acid. One of the compounds with the p-tolyl substitution was found to be most active in this study, and its cytotoxicity against two of the cell lines, MDA-MB 231 and A-549 were in tune with the standard compound, 5-fluorouracil.

Vancomycin conjugated iron oxide nanoparticles for magnetic targeting and efficient capture of Gram-positive and Gram-negative bacteria.

Drug conjugated iron oxide magnetite (Fe3O4) nanoparticles are of great interest in the field of biomedicine. In this study, vancomycin (Van) conjugated magnetite (Fe3O4) nanoparticles were envisioned to capture and inhibit the growth of bacteria. Hydrophobic Fe3O4 nanoparticles were synthesized by using co-precipitation of ferrous (Fe2+) and ferric (Fe3+) ions following a surface modification step with oleic acid as stabilizers. Thereafter, a ligand exchange technique was employed to displace oleic acid with hydrophilic dopamine (DOPA) molecules which have a catechol group for anchoring to the iron oxide surface to prepare water dispersible nanoparticles. The surface of the resulting Fe3O4/DOPA nanoparticles contains amino (-NH2) groups that are conjugated with vancomycin via a coupling reaction between the -NH2 group of dopamine and the -COOH group of vancomycin. The prepared vancomycin conjugated Fe3O4/DOPA nanoparticles were named Fe3O4/DOPA/Van and exhibited a magnetic response to an external magnetic field due to the presence of magnetite Fe3O4 in the core. The Fe3O4/DOPA/Van nanoparticles showed bactericidal activity against both Gram positive Bacillus subtilis (B. subtilis) and Streptococcus and Gram-negative bacteria Escherichia coli (E. coli). Maximum inhibition zones of 22 mm, 19 mm and 18 mm were found against B. subtilis, Streptococcus and E. coli respectively. Most importantly, the vancomycin conjugated nanoparticles were effectively bound to the cell wall of the bacteria, promoting bacterial separation and growth inhibition. Therefore, the prepared Fe3O4/DOPA/Van nanoparticles can be promising for effective bacterial separation and killing in the dispersion media.

Photooxidation Coupled Kabachnik-Fields and Bigenelli reactions for Direct Conversion of Benzyl alcohols to α-Amino Phosphonates and Dihydropyrimidones.

A tandem one-pot solvent free approach for the direct conversion of benzyl alcohols to α-amino phosphonates and dihydropyrimidones is reported. The method relies on a metal free photo-oxidation of benzyl alcohols to benzaldehydes under UV irradiation using ammonium perchlorate followed by Kabachnik-Fields and Biginelli reactions. The reaction conditions are moderate and metal free with good substrate scope. The control experiments were performed to investigate the role of the ammonium perchlorate and molecular oxygen as oxidants. The quenching experiments in the presence of TEMPO and other radical quenchers suggest radical based mechanism.

Synthesis and in vitro evaluation of substituted 3-cinnamoyl-4-hydroxy-pyran-2-one (CHP) in pursuit of new potential antituberculosis agents.

Tuberculosis is an ever-evolving infectious disease that urgently needs new drugs. In the search for new antituberculosis agents, a library of 3-cinnamoyl-4-hydroxy-6-methyl-2H-pyran-2-ones (CHPs) (2a-2y) was synthesized and evaluated against a standard virulent laboratory strain of Mycobacterium tuberculosis H37Rv. Out of 25 compounds, 11, 5, 7 and 2 (2a and 2u) showed least, moderate, good and appreciable activities, respectively, based on minimum inhibitory concentrations (MICs). Both 2a and 2u exhibited an MIC value of 4 µg ml-1, which was close to those of standard antituberculosis drugs ethambutol, streptomycin and levofloxacin. Neither 2a nor 2u showed any activity against Gram-positive or Gram-negative bacteria and even against non-tuberculous mycobacterium, i.e. Mycobacterium smegmatis. Thus, like the antituberculosis drugs rifampicin, isoniazid and pretomanid, they are highly TB specific. All the pyrone-based chalcones showed no recognizable level of cytotoxicity against normal human kidney cell line (HEK-293) up to 80 µM concentration and 11 exhibited an IC50 ≤ 100 µM (highest tested concentration). On further investigation, both 2a and 2u proved to be nontoxic against four human cell lines but 2a proved to be a better choice as it did not reach IC50 even at 100 µM (highest tested concentration) while the IC50 of 2u was around 80 µM. In conclusion, our results demonstrate that 2a is specific against M. tuberculosis with no appreciable toxicity; its activity matches that of some clinically approved antituberculosis drugs and it therefore merits further evaluation.

Synthesis and biological evaluation of novel 3-O-tethered triazoles of diosgenin as potent antiproliferative agents.

Diosgenin, a promising anticancer steroidal sapogenin, was isolated from Dioscorea deltoidea. Keeping its stereochemistry rich architecture intact, a scheme for the synthesis of novel diosgenin analogues was designed using Cu (I)-catalysed alkyne-azide cycloaddition in order to study their structure-activity relationship. Both diosgenin and its analogues exhibited interesting anti-proliferative effect against four human cancer cell lines viz. HBL-100 (breast), A549 (lung), HT-29 (colon) and HCT-116 (colon) using [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide] (MTT) assay. Among the synthesized analogues, Dgn-1 bearing a simple phenyl R moiety attached via triazole to the parent molecule was identified as the most potent analogue against A549 cancer cell line having IC50 of 5.54µM, better than the positive control (BEZ-235). Dgn-2 and Dgn-5 bearing o-nitrophenyl and o-cyanophenyl R moieties respectively, displayed impressive anti-proliferative activity against all the tested human cancer cell lines with IC50 values ranging from 5.77 to 9.44µM. The structure-activity relationship (SAR) revealed that the analogues with simple phenyl R moiety or electron withdrawing ortho substituted R moieties seem to have beneficial impact on the anti-proliferative activity.

Synthesis and biological evaluation of novel isoxazoles and triazoles linked 6-hydroxycoumarin as potent cytotoxic agents.

A new series of diverse isoxazoles and triazoles linked 6-hydroxycoumarin (1) were synthesized using click chemistry approach. All the derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) cytotoxicity screening against a panel of five different human cancer cell lines viz. prostate (PC-3), colon (HCT-116 and Colo-205), leukemia (HL-60) and lung (A-549) to check their cytotoxic potential. Interestingly, among the tested molecules, some of the analogs displayed better cytotoxic activity than the parent 6-hydroxycoumarin (1). Of the synthesized isoxazoles, compounds 10 and 13 showed the best activity with IC50 of 8.2 and 13.6 µM against PC-3 cancer cell line, while as, among the triazoles, compounds 23 and 25 were the most active with the IC50 of 10.2 and 12.6 µM against A-549 cancer cell line. The other derivatives showed almost comparable activity with that of the parent molecule. The present study resulted in identification of ortho substituted isoxazole and triazole derivatives of 6-hydroxycoumarin as effective cytotoxic agents against prostate (PC-3) and lung (A-549) cancer cell lines, respectively.