The present work reports on the synthesis, anti-Trypanosoma cruzi activities and docking studies of a novel series of 2-(pyridin-2-yl)-1,3-thiazoles derived from 2-pyridine thiosemicarbazone. The majority of these compounds are potent cruzain inhibitors and showed excellent inhibition on the trypomastigote form of the parasite, and the resulting structure-activity relationships are discussed. Together, these data present a novel series of thiazolyl hydrazones with potential effects against Chagas disease and they could be important leads in continuing development against Chagas disease.
The main protease (M
pro
, 3CL
pro
) of SARS-CoV-2 is an attractive
target in coronaviruses because of its crucial involvement in viral replication and
transcription. Here, we report on the design, synthesis, and structure–activity
relationships of novel small-molecule thioesters as SARS-CoV-2 M
pro
inhibitors. Compounds
3w
and
3x
exhibited excellent SARS-CoV-2
M
pro
inhibition with
k
inac
/
K
i
of 58,700
M
–1
s
–1
(
K
i
= 0.0141
μM) and 27,200 M
–1
s
–1
(
K
i
= 0.0332 μM), respectively. In Calu-3 and Vero76
cells, compounds
3h
,
3i, 3l
,
3r
,
3v
,
3w
, and
3x
displayed antiviral activity in the nanomolar
range without host cell toxicity. Co-crystallization of
3w
and
3af
with SARS-CoV-2 M
pro
was accomplished, and the X-ray
structures showed covalent binding with the catalytic Cys145 residue of the protease.
The potent SARS-CoV-2 Mpro inhibitors also inhibited the M
pro
of other
beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be
useful to treat a broader range of coronaviral infections.
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