The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development of new effective therapeutic interventions for the battle against SARS-CoV-2. A new series of
N
-(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle of the SARS-CoV Mpro co-crystallized WR1 inhibitor. Notably, compound
3b
achieved the most promising anti-SARS-CoV-2 activity with an IC
50
value of 174.7 µg/mL. On the other hand, compounds
3a
,
3b
, and
3c
showed very promising SARS-CoV-2 Mpro inhibitory effects with IC
50
values of 4.67, 5.12, and 11.90 µg/mL, respectively. Compound
3b
docking score was very promising (−6.94 kcal/mol) and its binding mode was nearly similar to that of WR1. Besides, the molecular dynamics (MD) simulations of compound
3b
showed its great stability inside the binding pocket until around 40 ns. Finally, a very promising SAR was concluded to help to design more powerful SARS-CoV-2 Mpro inhibitors shortly.
Chemical ligation via O- to N-acyl transfer of O-acylated serine containing peptides affords serine containing native peptides via 8- and 11-membered cyclic transition states opening the door to a wide variety of potential applications to peptide elaboration. The feasibility of these traceless chemical ligations is feasible as supported by computation.
Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.
Novel antibiotics
are urgently needed. The troponoids [tropones,
tropolones, and α-hydroxytropolones (α-HT)] can have anti-bacterial
activity. We synthesized or purchased 92 troponoids and evaluated
their antibacterial activities against Staphylococcus
aureus, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. Preliminary hits were assessed
for minimum inhibitory concentrations (MIC80) and cytotoxicity
(CC50) against human hepatoma cells. Sixteen troponoids
inhibited S. aureus/E. coli/A. baumannii growth by ≥80% growth at <30 μM with CC50 values >50 μM. Two selected tropolones (63 and 285) inhibited 18 methicillin-resistant S.
aureus (MRSA) strains with similar MIC80 values as against a reference strain. Two selected thiotropolones
(284 and 363) inhibited multidrug-resistant
(MDR) E. coli with MIC80 ≤30 μM. One α-HT (261) inhibited
MDR-A. baumannii with MIC80 ≤30 μM. This study opens new avenues for development
of novel troponoid antibiotics to address the critical need to combat
MDR bacterial infections.
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