A general method for the synthesis of a library of hitherto unreported amino-1,4-naphthoquinone-appended triazoles was accomplished via a sequential three-component reaction of substituted N-propargylaminonaphthoquinones with variously substituted alkyl bromides/2-bromonaphthalene-1,4-dione and sodium azide in the presence of Et3N/CuI in water. Aminonaphthoquinone-appended iminochromene-triazole hybrid heterocycles were also synthesized from the amino-1,4-naphthoquinone-appended-1,2,3-triazolylacetonitriles. All the triazole hybrids were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB). Among the triazoles, 2-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)(4-(trifluoromethyl)phenyl)amino)naphthalene-1,4-dione (7d) emerged as the most active one with IC50 = 1.87 μM, being more potent than the anti-TB drugs, cycloserine (6 times), pyrimethamine (20 times) and equipotent as the drug ethambutol (IC50
A drug-inorganic nanostructured material involving pharmaceutically active compound lawsone intercalated Zn-Al layered double hydroxides (Law-LDHs) with Zn/AI = 4 has been assembled by co-precipitation and ion exchange methods. Powder X-ray diffraction (XRD) and Fourier transform infrared spectra (FTIR) analysis indicate a successful intercalation of lawsone between the layers of layered double hydroxides. It suggests that layered double hydroxides may have application as the basis of a drug delivery system.
The aim of this study was to prepare a lipid-based self-microemulsifying drug delivery system (SMEDDS) to increase the solubility and oral bioavailability of a poorly water-soluble compound, buparvaquone (BPQ).
A simple, sensitive and specific reversed-phase high-performance liquid chromatographic method with UV detection at 251 nm was developed for quantitation of buparvaquone (BPQ) in human and rabbit plasma. The method utilizes 250 microL of plasma and sample preparation involves protein precipitation followed by solid-phase extraction. The method was validated on a C18 column with mobile phase consisting of ammonium acetate buffer (0.02 m, pH 3.0) and acetonitrile in the ratio of 18:82 (v/v) at a flow rate of 1.1 mL/min. The calibration curves were linear (correlation coefficient>or=0.998) in the selected range. The method is specific and sensitive with limit of quantitation of 50 ng/mL for BPQ. The validated method was found to be accurate and precise in the working calibration range. Stability studies were carried out at different storage conditions and BPQ was found to be stable. Partial validation studies were carried out using rabbit plasma and intra- and inter-day precision and accuracy were within 7%. This method is simple, reliable and can be routinely used for preclinical pharmacokinetic studies for BPQ.
A series of dimeric naphthoquinones containing natural 2-hydroxy-1-4-naphthoquinone moiety was designed, synthesized, and evaluated against neuraminidase of H5N1 virus. p-hydroxy derivatives showed higher inhibition when compared to p-halogenated compounds. Molecular docking studies conducted with H5N1 neuraminidase clearly demonstrated different binding modes of the most active compound onto the open and closed conformations of loop 150. The results thus provide not only evidences of a novel scaffold evaluated as inhibitor, but also a rational explanation involving molecular modeling and the role of loop 150 in the binding.
Three metal(II) complexes [CoLCl2], [CuLCl2] and [ZnL2Cl2] {L = 2‑chloro‑3‑((3‑dimethylamino)propylamino)naphthalene‑1,4‑dione} have been synthesized and characterized using analytical, thermal and spectral techniques (FT-IR, UV-Vis, ESR and ESI-MS). The structure of the L has been confirmed by single crystal XRD study. The complexes show good binding propensity to bovine serum albumin (BSA) having relatively higher binding constant values (104 M-1) than the ligand. Fluorescence spectral studies indicate that [CoLCl2] binds relatively stronger with CT DNA through intercalative mode, exhibiting higher binding constant (2.22 × 105 M-1). Agarose gel electrophoresis run on plasmid DNA (pUC18) prove that all the complexes showed efficient DNA cleavage via hydroxyl radical mechanism. The complexes were identified as potent anticancer agents against two human cancer cell lines (MCF7 and A549) by comparing with cisplatin. Co(II) complex demonstrated greater cytotoxicity against MCF7 and A549 cells with IC50 values at 19 and 22 μM, respectively.
Dichloromethane extracts of the root bark and stem bark of Kigelia pinnata collected from Zimbabwe exhibited antitrypanosomal activity against Trypanosoma brucei brucei in vitro. Activity-guided fractionation led to the isolation of four naphthoquinones from both the root and stem bark of the plant. The compounds were identified as 2-(1-hydroxyethyl)-naphtho[2,3-b]furan-4,9-quinone (1), isopinnatal (2), kigelinol (3), and isokigelinol (4). Subsequently, the compounds were assessed for antitrypanosomal activity against T. brucei brucei and T. brucei rhodesiense bloodstream form trypomastigotes in vitro. Compound 1 with a furanonaphthoquinone structure was found to possess pronounced activity against both parasites with IC50 values of 0.12 and 0.045 microM, respectively, although it was less active than the standard drug pentamidine. Compounds 2, 3, and 4 also exhibited activity against the parasites, although to a lesser extent. The activities of the compounds were further assessed by comparison with the cytotoxic activities obtained against KB cell lines.
Two new naphthoquinones designated as 3alpha-hydroxy-2-(2-hydroxypropan-2-yI)-9alpha-methoxy-2,3,3alpha,9alpha-tetra-hydronaphtho[2,3-b]furan-4,9-dione (callicarpa-quinone A, 1) and 5-hydroxy-2-(2-hydroxypropan-2-yl)naphtho[2,3-b]furan-4,9-dione (callicarpaquinone B, 2) were isolated from the chloroform fraction of Callicarpa maingayi. Three other known compounds, identified as avicequinone-C (3), wodeshiol (4) and paulownin (5), were reported for the first time from this species. The structure elucidation of compounds was established by comprehensive 1D and 2D NMR spectroscopic analyses as well as EIMS, UV and IR spectral data. Compounds 1 and 2 were tested in vitro for their cytotoxic activity against human breast cancer MCF-7cells. Compound 2 exhibited strong cytotoxic activity with an IC50 value of 1.9 +/- 0.2 microM, while 1 showed moderate activity with an IC50 value of 25.0 +/- 4.3 microM.
A simple, sensitive and specific reversed phase high performance liquid chromatographic (RP-HPLC) method with UV detection at 251 nm was developed for simultaneous quantitation of buparvaquone (BPQ), atenolol, propranolol, quinidine and verapamil. The method was applicable in rat in situ intestinal permeability study to assess intestinal permeability of BPQ, a promising lead compound for Leishmania donovani infections. The method was validated on a C-4 column with mobile phase comprising ammonium acetate buffer (0.02 M, pH 3.5) and acetonitrile in the ratio of 30:70 (v/v) at a flow rate of 1.0 ml/min. The retention times for atenolol, quinidine, propranolol, verapamil and BPQ were 4.30, 5.96, 6.55, 7.98 and 8.54 min, respectively. The calibration curves were linear (correlation coefficient > or =0.996) in the selected range of each analyte. The method is specific and sensitive with limit of quantitation of 15 microg/ml for atenolol, 0.8 microg/ml for quinidine, 5 microg/ml for propranolol, 10 microg/ml for verapamil and 200 ng/ml for BPQ. The validated method was found to be accurate and precise in the working calibration range. Stability studies were carried out at different storage conditions and all the analytes were found to be stable. This method is simple, reliable and can be routinely used for accurate permeability characterization.
Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles.