5 research outputs found
Clicking 3′-Azidothymidine into Novel Potent Inhibitors of Human Immunodeficiency Virus
3′-Azidothymidine
(AZT) was the first approved antiviral for the treatment of human
immunodeficiency virus (HIV). Reported efforts in clicking the 3′-azido
group of AZT have not yielded 1,2,3-triazoles active against HIV or
any other viruses. We report herein the first AZT-derived 1,2,3-triazoles
with submicromolar potencies against HIV-1. The observed antiviral
activities from the cytopathic effect (CPE) based assay were confirmed
through a single replication cycle assay. Structure–activity-relationship
(SAR) studies revealed two structural features key to antiviral activity:
a bulky aromatic ring and the 1,5-substitution pattern on the triazole.
Biochemical analysis of the corresponding triphosphates showed lower
ATP-mediated nucleotide excision efficiency compared to AZT, which
along with molecular modeling suggests a mechanism of preferred translocation
of triazoles into the P-site of HIV reverse transcriptase (RT). This
mechanism is corroborated with the observed reduction of fold resistance
of the triazole analogue to an AZT-resistant HIV variant (9-fold compared
to 56-fold with AZT)
Toward Biophysical Probes for the 5-HT<sub>3</sub> Receptor: Structure−Activity Relationship Study of Granisetron Derivatives
This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT<sub>3</sub>A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT<sub>3</sub>A receptors in mammalian cells
Toward Biophysical Probes for the 5-HT<sub>3</sub> Receptor: Structure−Activity Relationship Study of Granisetron Derivatives
This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT<sub>3</sub>A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT<sub>3</sub>A receptors in mammalian cells
Design, Synthesis, Biochemical, and Antiviral Evaluations of C6 Benzyl and C6 Biarylmethyl Substituted 2‑Hydroxylisoquinoline-1,3-diones: Dual Inhibition against HIV Reverse Transcriptase-Associated RNase H and Polymerase with Antiviral Activities
Reverse transcriptase (RT) associated
ribonuclease H (RNase H) remains the only virally encoded enzymatic
function not targeted by current chemotherapy against human immunodeficiency
virus (HIV). Although numerous chemotypes have been reported to inhibit
HIV RNase H biochemically, few show significant antiviral activity
against HIV. We report herein the design, synthesis, and biological
evaluations of a novel variant of 2-hydroxyisoquinoline-1,3-dione
(HID) scaffold featuring a crucial C-6 benzyl or biarylmethyl moiety.
The synthesis involved a recently reported metal-free direct benzylation
between tosylhydrazone and boronic acid, which allowed the generation
of structural diversity for the hydrophobic aromatic region. Biochemical
studies showed that the C-6 benzyl and biarylmethyl HID analogues,
previously unknown chemotypes, consistently inhibited HIV RT-associated
RNase H and polymerase with IC<sub>50</sub>s in low to submicromolar
range. The observed dual inhibitory activity remained uncompromised
against RT mutants resistant to non-nucleoside RT inhibitors (NNRTIs),
suggesting the involvement of binding site(s) other than the NNRTI
binding pocket. Intriguingly, these same compounds inhibited the polymerase,
but not the RNase H function of Moloney Murine Leukemia Virus (MoMLV)
RT and also inhibited Escherichia coli RNase H. Additional biochemical testing revealed a substantially
reduced level of inhibition against HIV integrase. Molecular docking
corroborates favorable binding of these analogues to the active site
of HIV RNase H. Finally, a number of these analogues also demonstrated
antiviral activity at low micromolar concentrations
5‑Arylidenethioxothiazolidinones as Inhibitors of Tyrosyl–DNA Phosphodiesterase I
Tyrosyl–DNA phosphodiesterase I (Tdp1) is a cellular
enzyme
that repairs the irreversible topoisomerase I (Top1)–DNA complexes
and confers chemotherapeutic resistance to Top1 inhibitors. Inhibiting
Tdp1 provides an attractive approach to potentiating clinically used
Top1 inhibitors. However, despite recent efforts in studying Tdp1
as a therapeutic target, its inhibition remains poorly understood
and largely underexplored. We describe herein the discovery of arylidene
thioxothiazolidinone as a scaffold for potent Tdp1 inhibitors based
on an initial tyrphostin lead compound <b>8</b>. Through structure–activity
relationship (SAR) studies we demonstrated that arylidene thioxothiazolidinones
inhibit Tdp1 and identified compound <b>50</b> as a submicromolar
inhibitor of Tdp1 (IC<sub>50</sub> = 0.87 μM). Molecular modeling
provided insight into key interactions essential for observed activities.
Some derivatives were also active against endogenous Tdp1 in whole
cell extracts. These findings contribute to advancing the understanding
on Tdp1 inhibition