The continuous spread of SARS-CoV-2 calls for more direct-acting antiviral agents to
combat the highly infectious variants. The main protease (M
pro
) is an
promising target for anti-SARS-CoV-2 drug design. Here, we report the discovery of
potent non-covalent non-peptide M
pro
inhibitors featuring a
1,2,4-trisubstituted piperazine scaffold. We systematically modified the non-covalent
hit MCULE-5948770040 by structure-based rational design combined with multi-site binding
and privileged structure assembly strategies. The optimized compound
GC-14
inhibits M
pro
with high potency (IC
50
= 0.40 μM) and
displays excellent antiviral activity (EC
50
= 1.1 μM), being more
potent than Remdesivir. Notably,
GC-14
exhibits low cytotoxicity
(CC
50
> 100 μM) and excellent target selectivity for SARS-CoV-2
M
pro
(IC
50
> 50 μM for cathepsins B, F, K, L, and
caspase 3). X-ray co-crystal structures prove that the inhibitors occupy multiple
subpockets by critical non-covalent interactions. These studies may provide a basis for
developing a more efficient and safer therapy for COVID-19.
There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead K-5a2 led to the identification of a potent inhibitor 16c. 16c yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of 16c toward the NNRTI-adjacent site as a lead development strategy. Furthermore, 16c demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of 16c as a promising anti-HIV-1 drug candidate.
An improved synthesis of (S)-ketamine (esketamine) has been developed, which was cost-effective, and the undesired isomer could be recovered by racemization. Critical process parameters of each step were identified as well as the process-related impurities. The formation mechanisms and control strategies of most impurities were first discussed. Moreover, the (S)-ketamine tartrate is a dihydrate, which was disclosed for the first time. The practicable racemization catalyzed by aluminum chloride was carried out in quantitative yield with 99% purity. The ICH-grade quality (S)-ketamine hydrochloride was obtained in 51.1% overall yield (14.0% without racemization) by chiral resolution with three times recycling of the mother liquors. The robust process of esketamine could be industrially scalable.
Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.
The
spread of SARS-CoV-2 keeps threatening human life and health,
and small-molecule antivirals are in demand. The main protease (Mpro) is an effective and highly conserved target for anti-SARS-CoV-2
drug design. Herein, we report the discovery of potent covalent non-peptide-derived
Mpro inhibitors. A series of covalent compounds with a
piperazine scaffold containing different warheads were designed and
synthesized. Among them, GD-9 was identified as the most
potent compound with a significant enzymatic inhibition of Mpro (IC50 = 0.18 μM) and good antiviral potency against
SARS-CoV-2 (EC50 = 2.64 μM), similar to that of remdesivir
(EC50 = 2.27 μM). Additionally, GD-9 presented favorable target selectivity for SARS-CoV-2 Mpro versus human cysteine proteases. The X-ray co-crystal structure
confirmed our original design concept showing that GD-9 covalently binds to the active site of Mpro. Our nonpeptidic
covalent inhibitors provide a basis for the future development of
more efficient COVID-19 therapeutics.
The first detailed
description of the Lewis acid-catalyzed racemization
of (R)-ketamine is reported. A process for racemization
of the undesired (R)-ketamine enantiomer produced
from the resolution for preparing the NMDA receptor antagonist (S)-ketamine was developed in quantitative yield with 99%
chemical purity in the presence of a Lewis acid at 150 °C. Varying
degrees of racemization were observed in the presence of various frequently
used Lewis acids separately, and the catalytic efficiencies were arranged
as follows: MgCl2 ≈ AlCl3 > FeCl3 > ZnCl2 > BF3 > CaCl2. The
racemized ketamine was subsequently resolved using l-(+)-tartaric
acid to obtain (S)-ketamine in 41% yield with 99.5%
ee. Such a concise and cost-efficient approach for the racemization
can be industrially useful to recycle the waste (R)-ketamine enantiomer into the resolution process to obtain (S)-ketamine.
Here,
we report the design, synthesis, structure–activity
relationship studies, antiviral activity, enzyme inhibition, and druggability
evaluation of dihydrofuro[3,4-d]pyrimidine derivatives
as a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors
(NNRTIs). Compounds 14b (EC50 = 5.79–28.3
nM) and 16c (EC50 = 2.85–18.0 nM) exhibited
superior potency against a panel of HIV-1-resistant strains. Especially,
for the changeling mutations F227L/V106A and K103N/Y181C, both compounds
exhibited remarkably improved activity compared to those of etravirine
and rilpivirine. Moreover, 14b and 16c showed
moderate RT enzyme inhibition (IC50 = 0.14–0.15
μM), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, 14b and 16c exhibited favorable pharmacokinetic
and safety properties, making them excellent leads for further development.
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