3 research outputs found
Mechanism and Site of Inhibition of AMPA Receptors: Substitution of One and Two Methyl Groups at the 4‑Aminophenyl Ring of 2,3-Benzodiazepine and Implications in the “E” Site
2,3-Benzodiazepines
are a well-known group of compounds for their
potential antagonism against AMPA receptors. It has been previously
reported that the inhibitory effect of 2,3-benzodiazepine derivatives
with a 7,8-ethylenedioxy moiety can be enhanced by simply adding a
chlorine atom at position 3 of the 4-aminophenyl ring. Here we report
that adding a methyl group at position 3 on the 4-aminophenyl ring,
termed as BDZ-11-7, can similarly enhance the inhibitory activity,
as compared with the unsubstituted one or BDZ-11-2. Our kinetic studies
have shown that BDZ-11-7 is a noncompetitive antagonist of GluA2Q
homomeric receptors and prefers to inhibit the closed-channel state.
However, adding another methyl group at position 5 on the 4-aminophenyl
ring, termed as BDZ-11-6, fails to yield extra inhibition on GluA2Q
receptors. Instead, BDZ-11-6 exhibits a diminished inhibition of GluA2Q.
Site interaction test indicates the two compounds, BDZ-11-6 and BDZ-11-7,
bind to the same site on GluA2Q, which is also the binding site for
their prototype, BDZ-11-2. Based on the results from this and our
earlier studies, we propose that the binding site that accommodates
the 4-aminophenyl ring must contain two interactive points, with one
preferring polar groups like chlorine and the other preferring nonpolar
groups such as a methyl group. Either adding a chlorine or a methyl
group may enhance the inhibitory activity of 2,3-benzodiazepine derivatives
with a 7,8-ethylenedioxy moiety. Adding any two of the same group
on positions 3 and 5 of the 4-aminophenyl ring, however, significantly
reduces the interaction between these 2,3-benzodiazepines and their
binding site, because one group is always repelled by one interactive
point. We predict therefore that adding a chlorine atom at position
3 and a methyl group at position 5 of the 4-aminophenyl ring of 2,3-benzodiazepine
derivatives with a 7,8-ethylenedioxy moiety may produce a new compound
that is more potent
Drug combination studies of curcumin and genistein against rhodesain of <i>Trypanosoma brucei rhodesiense</i>
<p>Curcumin and genistein are two natural products obtained from <i>Curcuma longa</i> L. and soybeans, endowed with many biological properties. Within the last years they were shown to possess also a promising antitrypanosomal activity. In the present paper, we investigated the activity of both curcumin and genistein against rhodesain, the main cysteine protease of <i>Trypanosoma brucei rhodesiense</i>; drug combination studies, according to Chou and Talalay method, allowed us to demonstrate a potent synergistic effect for the combination curcumin-genistein. As a matter of fact, with our experiments we observed that the combination index of curcumin-genistein is < 1 for the reduction from 10 to 90% of rhodesain activity.</p
Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain‑2 for the Treatment of Neglected Tropical Diseases (NTDs)
This paper describes
the development of a class of peptide-based
inhibitors as novel antitrypanosomal and antimalarial agents. The
inhibitors are based on a characteristic peptide sequence for the
inhibition of the cysteine proteases rhodesain of Trypanosoma
brucei rhodesiense and falcipain-2 of Plasmodium falciparum. We exploited the reactivity
of novel unsaturated electrophilic functions such as vinyl-sulfones,
-ketones, -esters, and -nitriles. The Michael acceptors inhibited
both rhodesain and falcipain-2, at nanomolar and micromolar levels,
respectively. In particular, the vinyl ketone <b>3b</b> has
emerged as a potent rhodesain inhibitor (<i>k</i><sub>2nd</sub> = 67 × 10<sup>6</sup> M<sup>–1</sup> min<sup>–1</sup>), endowed with a picomolar binding affinity (<i>K</i><sub>i</sub> = 38 pM), coupled with a single-digit micromolar activity
against Trypanosoma brucei brucei (EC<sub>50</sub> = 2.97 ÎĽM), thus being considered as a novel lead
compound for the discovery of novel effective antitrypanosomal agents