8 research outputs found
Synthesis and Anti-HCV Activity of 4‑Hydroxyamino α‑Pyranone Carboxamide Analogues
High genetic variability in hepatitis
C virus (HCV), emergence of drug resistant viruses and side effects
demand the requirement for development of new scaffolds to show an
alternate mechanism. Herein, we report discovery of new scaffold <b>I</b> based on 4-hydroxyamino α-pyranone carboxamide as
promising anti-HCV agents. A comprehensive structure–activity
relationship (SAR) was explored with several newly synthesized compounds.
In all promising compounds (<b>17</b>–<b>19</b>, <b>21</b>–<b>22</b>, <b>24</b>–<b>25</b>, and <b>49</b>) with EC<sub>50</sub> ranging 0.15
to 0.40 μM, the aryl group at C-6 position of α-pyranone
were unsubstituted. In particular, <b>25</b> demonstrated potential
anti-HCV activity with EC<sub>50</sub> of 0.18 μM in cell based
HCV replicon system with lower cytotoxicity (CC<sub>50</sub> >
20 μM) and provided a new scaffold for anti-HCV drug development.
Further investigations, including biochemical characterization, are
yet to be performed to elucidate its possible mode of action
Sequential Pd(0)/Fe(III) Catalyzed Azide–Isocyanide Coupling/Cyclization Reaction: One-Pot Synthesis of Aminotetrazoles
A rapid
and efficient synthesis of aminotetrazole from aryl azides,
isocyanides, and TMSN<sub>3</sub> is developed. The reaction is promoted
by sequential Pd(0)/FeÂ(III) catalysis. The reaction sequence utilizes
the Pd-catalyzed azide–isocyanide denitrogenative coupling
reaction to generate unsymmetric carbodiimide <i>in situ</i>, which reacts with TMSN<sub>3</sub> in the presence of FeCl<sub>3</sub> in a single pot. The methodology has distinct advantages
over traditional synthetic approaches where toxic Hg and Pb salts
are employed at stoichiometric scale
Stable Tricyclic Antitubercular Ozonides Derived from Artemisinin
New, highly stable tricyclic antitubercular
ozonides <b>9</b> and <b>10</b> derived from artemisinin
are reported in 39
and 9% yields, respectively. The ozonide groups of <b>9</b> and <b>10</b> were found to be stable under strong basic and acidic conditions.
The absolute configuration of ozonides <b>9</b> was confirmed
by X-ray crystallography. Ozonide <b>10</b> shows promising
antitubercular activity against <i>M. tuberculosis</i> H<sub>37</sub>Ra and <i>M. tuberculosis</i> H<sub>37</sub>Rv
with MIC values of 0.39 and 3.12 μg/mL, respectively
Sequential Pd(0)/Fe(III) Catalyzed Azide–Isocyanide Coupling/Cyclization Reaction: One-Pot Synthesis of Aminotetrazoles
A rapid
and efficient synthesis of aminotetrazole from aryl azides,
isocyanides, and TMSN<sub>3</sub> is developed. The reaction is promoted
by sequential Pd(0)/FeÂ(III) catalysis. The reaction sequence utilizes
the Pd-catalyzed azide–isocyanide denitrogenative coupling
reaction to generate unsymmetric carbodiimide <i>in situ</i>, which reacts with TMSN<sub>3</sub> in the presence of FeCl<sub>3</sub> in a single pot. The methodology has distinct advantages
over traditional synthetic approaches where toxic Hg and Pb salts
are employed at stoichiometric scale
<i>In</i><i>vivo</i> efficacy of
<p>HM. BALB/c mice were fed with HM (0.25 or 0.5 mg/kg) or ACV (5 mg/kg) and after 8 h of drug treatment the animals were infected with HSV-2G (9 X 10<sup>5</sup> pfu per animal) intravaginally. The challenged animals of test groups were fed with HM twice daily for 7 days. Development of lesions and death were observed three times daily, while brain and vaginal tissue were collected after sacrification on days 2, 4, 6 or 8 after infection, homogenized and centrifuged. The supernatant was used for the determination of virus yield by plaque assay. Mean lesion score [A], Mean±S.D. of virus yield at log<sub>10</sub> (PFU/organ) in vaginal tissue [B] and brain [C]. </p
Anti-HSV efficacy of HM.
<p>[A] <b>Plaque </b><b>Reduction </b><b>Assay</b>. Infected cells were treated with HM or ACV at 0.5-50 μg/ml, overlaid with methylcellulose and plaques developed after 2-3 days were stained. The % of plaque number reduction was calculated, and the effective concentration of drug that inhibited the number of viral plaques was interpolated from the dose-response curve. [B] <b>Time </b><b>course </b><b>analysis</b>. Inhibitory effects of HM and ACV at various time points prior to infection (-3 to -1 h), at the time of infection (0 h) and post-infection (2-24 h) with HSV-2 were evaluated by plaque reduction assay. Each bar represents the mean ± S.E.M of three independent experiments.</p
Histopathology of Genital tissue of Balb/C mice
<p>: uninfected [A], infected with HSV-2G [B], HSV-2G infected animals treated with 0.5 µg/ml of HM [C], and ACV at 5 µg/ml [D]. </p
Effect of HM on viral IE transcriptional events.
<p>[A] <b>EMSA</b>: HSV-2G infected Vero cells were treated with HM for 2 and 4 h and assayed for EMSA. Biotin-labelled oligo was present in Lanes 1-6; P, biotin labelled oligo, M, mock control. [B] <b>Supershift </b><b>assay</b>: nuclear extracts from HSV-2G infected HM treated cells for 4 h p.i. was pre-incubated with HCF-1 polyclonal antibodies, added with reaction mixture, applied to non-denaturing 4% polyacrylamide gels and visualized by autoradiography. P, free biotin labelled probe; ns, nonspecific binding. [C] HCF-1 or LSD1 were immunoprecipitated in HM treated virus infected Vero cell lysate and the association was confirmed by immunoblotting with anti-HCF-1 and anti-LSD1 antibodies. </p