Publications

As part of our studies to discover new HIV-1 reverse transcriptase inhibitors, a series of 3,4-dichlorophenyl substituted 1,2,3-thiadiazole thioacetanilide (TTA=[(1,2,3-thiadiazole-5-yl)sulfanyl]acetanilide) derivatives were synthesized, and in vitro anti-HIV activity was evaluated. The results revealed that nearly half of the compounds show moderate-to-good inhibitory potency against HIV-1. In particular, compound 7f is highly potent, with an EC(50) value of 0.95+/-0.33 microM. The preliminary structure-activity relationship among the newly synthesized congeners is discussed.

A human immunodeficiency virus type 1 (HIV-1)-seropositive patient was treated sequentially with the dideoxynucleoside (ddN) analogues zidovudine, didanosine, zalcitabine, stavudine, and lamivudine and the nonnucleoside HIV-1-specific reverse transcriptase inhibitor (NNRTI) loviride (alpha-APA). Accumulation of drug resistance mutations (mainly V75I, F77L, K103N, F116Y, Q151M, and M184V) eventually resulted in a strain that was genotypically and phenotypically resistant to all tested ddNs and the majority of NNRTIs. However, the multidrug-resistant virus retained wild type sensitivities to drugs such as foscarnet, phosphonomethoxyethyl adenine, dextran sulfate, JM3100, saquinavir, and NNRTI TSAO-m3T. Drug-resistant isolates showed replication kinetics and infectivity in an in vitro peripheral blood mononuclear cell system similar to those of the wild type isolate from the same patient. The multi-ddN-resistant isolate was not eliminated in a competition culture with the wild type isolate. Sequential therapy did not prevent the appearance of multidrug-resistant virus with a conserved replication rate.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Reaction of 3-C-Methyl-1,2-O-isopropylidene-α-D-ribo-pentodialdo-1,4-furanose (8a) with leuco-quinizarin (2,3,4a,9a-tetrahydroanthracene-1,4,9,10-tetraone)(1a) in alkaline solution followed by aerial oxidation gave mainly (5S)-3-C-methyl 1,2-O-isopropylidene-5-(quinizarin-2-yl)-α-D-ribofur-anose (9a), acid hydrolysis of which gave the quinizarinylpyranose (14a). Similarly 3-O-benzyl-3-C-methyl-1,2-O-isopropylidene-α-D-ribopentodialdo-1,4-furanose (8b) and leucoquinizarin gave the (5S)-1,4-furanose derivative (9c) from which the (5S)-O-benzyl quinizarinyi pyranose (14b) was obtained. In contrast, the O-benzylfuranose (8b) with leucoquinizarin and DBU gave a mixture of (5R) and (5S)3-O-benzyl-3-C-methyl-1,2-O-isopropylidene-5-(quinizarin-2-yl)-α-D-ribofuranose (9d) and (9c) respectively. The (5R)-derivative produced the (5R) quinizarinylpyranose (15a) from which the corresponding (10R)-anthracyclinone (19c) was obtained. Similarly the (10S)-anthracyclinones (19a) and (19b) respectively were prepared from (9a) and (9c) respectively, and the latter was debenzylated with boron trichloride to produce (19a). In a similar manner the O-benzyl aldehyde sugar (8b) with 5-hydroxyleucoquinizarin (1b) in DMF with DBN gave after aerial oxidation the (5R), (5S) and related 5-deoxy hydroxyglycitylanthraquinones (9e), (9f), and (9g) respectively. Each of these was converted into the corresponding (10R), (10S), and (10R) 7-deoxy-4-hydroxyanthracyclinones (19i), (19j), and (19h) by the same general series of reactions outlined above. Structures of the compounds were confirmed by UV, mass, IR, CD, and 1H NMR spectroscopy.

Aluminum-diamond composites were produced using selective laser melting (SLM) from mechanically mixed diamond and Al12Si powders for use in thermal management applications. The feasibility of SLM for both interface tailoring and simultaneously densification, which are the key for determining the overall thermal conductivity (TC) of the composites, has been investigated. The results indicate that the interface structure of the as-built composites can be controlled, despite the complex physical and chemical nature of SLM. A ‘clean’ diffusion-bonded interface revealed at the micron scale, which is desirable for enhancing TC, was obtained at a laser energy density of 95.2 J/mm3. This demonstrates a possible new potential of SLM in creating metal matrix composites for functional applications. However, despite manipulation of the processing parameters, it was not possible to achieve a relative density above 90%. Thus, how to realize near full density, while maintaining such a ‘clean’ interface during SLM remains a key technical problem for the future. The complex metallurgical mechanisms responsible for interface evolution and microstructure formation are discussed in detail with the aid of finite element analysis, and further densification strategies are proposed.

Early responses of elevated cytokines such as IL-6 reflect the active immune responses, leading to high titers of IgG antibodies against COVID-19.

The in vivo activity of the Keggin polyoxotungstate PM-19 [K 7 (PTi 2 W 10 O 40 )·6H 2 O] was investigated against herpes simplex virus type 2 (HSV-2) in ddY mice. A single dose of PM-19 at 100mg kg −1 administered intraperitoneally (i.p.) immediately after i.p. infection of ddY mice with HSV-2 offered 92% protection against an otherwise lethal HSV-2 infection. PM-19 was less or not effective if given by any route other than the i.p. route. When repeated doses of PM-19 were administered i.p. on day 0 (immediately after infection) and day 1 and 2 after infection, it proved protective over a dosage range of 0.1-50 mg kg −1 day −1 , its ED 50 (50% effective dose, based on the number of survivors) being 0.25 mg kg −1 day −1 . Under these conditions, ACV was not effective even at doses up to 100 mg kg −1 day −1 .

The requirements for active-site binding of thymidylate synthase from three sources, Lactobacillus casei, murine leukemia L1210, and human lymphoblast (Molt/4F), were investigated by analyzing the binding of a series of 5-(p-substituted phenyl)-2'-deoxyuridylates (N1-substituted 5-aryl-2, 4-dioxopyrimidines) to the enzyme. Multiple regression analysis revealed that an increase in electron density of the heterocyclic ring and hydrophobic substituents enhance affinity. Correlations of biological results with spectral data indicated that higher electron densities at the oxygen atoms are responsible for increase in binding. These results support the presence of both a cationic binding site and a hydrophobic region. In addition, the results revealed an unusual reversal of electronic requirements for binding and catalysis. The formation of the binary complex is enhanced by electron-donating substituents, while the initial catalytic reaction, formation of the covalent ternary complex, is promoted and stabilized by electron-withdrawing substituents.

The 2-phenyl-benzoxazin-4-ones were condensed with primary amine to form the 2,3-disubstituted quinazolin-4(3H)-ones. Their chemical structure was elucidated by means of spectral (FT-IR, 1H-NMR, MS) and elemental analysis. The antiviral activity and cytotoxicity of the compounds were tested in HeLa cells (vesicular stomatitis virus, Coxsackie virus B4 and respiratory syncytial virus), HEL cells [herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), vaccinia virus], Vero cells (parainfluenza-3, reovirus-1, Sindbis virus, Coxsackie virus B4 and Punta Toro virus). Among the new derivatives evaluated, specific antiviral activity was noted with compound QAA against vaccinia virus, parainfluenza-3 virus and Punta Toro virus, compound QOPD against HSV-1, HSV-2 and vaccinia virus, and compounds QONA and PD-NFIN against Coxsackie virus B4.   Key words:  Quinazoline, antiviral, HSV, vaccinia, sulphanamides.