•Twenty-one novel 2,4,5-trisubstituted thiazoles were designed and synthesized.•Reasonable design and combination of optimal substituents increased the activity.•SAR exploration focused on positions 4 and 5 of the thiazole ring.•Some compounds showed inhibition against both WT and some mutant viruses.In our previous work, novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were synthesized, and their activities were evaluated against HIV-1 reverse transcriptase. Some interesting results were obtained, which led us to a new discovery regarding these TSTs. In the present study, 21 new 2,4,5-trisubstituted thiazole derivatives were rationally designed and synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) in accordance with our previous study. Among the synthesized target compounds, compounds 14, 16, 17, and 19 showed more potent inhibitory activities against HIV-1 with an IC50 value of 0.010 μM. Compounds 4, 9, 10, 11, 13 and 16 were further tested on nine NNRTI-resistant HIV-1 strains, and all of these compounds exhibited inhibitory effects. A molecular docking study was conducted, and the results showed a consistent and stable binding mode for the typical compounds. These results have provided deeper insights and SAR of these types of NNRTIs.

Influenza viral infection of the host begins by the attachment of viral hemagglutinin to a cell surface receptor. In the current study, a hemagglutinin fragment peptide library was screened using an H5N1 recombinant pseudotyped viral system. One peptide, designated HA-pep25, showed effective antiviral activity against both human and avian influenza viral strains (IC50 = 12.0–51.0 μM). A mechanistic study demonstrated direct binding between HA-pep25 and sialyllactose, which mimics the host receptor for the influenza virus. This binding was independent of the presence of sialic acid on the cell membrane. By generating alanine substitutions in HA-pep25, eight residues were identified as essential for the peptide’s anti-influenza activity. HA-pep25 derived from hemagglutinin blocked influenza viral entry by shielding the host receptor on the cell membrane. This peptide might be a candidate drug for influenza virus entry inhibition and may be combined with other antivirals targeting different steps of the influenza viral life cycle.Keywords: entry inhibitor; hemagglutinin; host; influenza; peptide

•2,4,5-Trisubstituted thiazole, a novel scaffold as NNRTIs.•30 compounds inhibited HIV-1 replication with IC50 0.046–9.59 μM.•Compounds 8, 9, 21, 23, 24 showed inhibition against WT and seven common mutants.•We studied the SAR and the possible binding mode of this type NNRTIs.•The 3D-QSAR results gave the further direction to the research.Novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were designed and synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Among the thirty-eight synthesized target compounds, thirty TSTs showed potent inhibition against HIV-1 replication in wild type HIV-1 at submicromolar concentrations (from 0.046 to 9.59 μM). Compounds 21, 23 and 24 were also tested on seven NNRTI-resistant HIV-1 strains, and all exhibited inhibitory effects with fold changes in IC50 ranging from 2.6 to 111, which were better than those of nevirapine (15.6-fold–371-fold). Docking simulations of compound 24 revealed a reasonable mechanism for the binding mode, and three-dimensional quantitative structure activity relationship (3-DQSAR) studies on this novel series of TST further elucidated the structure–activity relationship (SAR). The results suggested the great potential of TSTs as a novel class of NNRTIs with antiviral efficacy and a good resistance profile.

A series of novel N4-substituted thiophen-3-ylsulfonylquinoxalinone derivatives were designed and synthesized by variations of 2- and 5-position of the thiophene ring. All target molecules were tested for their anti-HIV-1 replication activities and compounds 1b and 1d were found to be the most potent inhibitors with an IC50 value at 10−8 mol L−1 level. The preliminary structure–activity relationships were analyzed on the basis of the binding mode of compound 1b predicted by CDOCKER.

Seven new phenylspirodrimanes, named stachybotrins D–F (1, 3, 4), stachybocins E and F (5, 6), and stachybosides A and B (7, 8), and four known compounds (2, 9–11), were isolated from the sponge-derived fungus Stachybotrys chartarum MXH-X73. Their structures were determined by detailed analysis of spectroscopic data. The absolute configurations of 1–8 were determined by chemical hydrolysis and modified Mosher’s and Marfey’s methods. All compounds were tested in an anti-HIV activity assay, and compound 1 showed an inhibitory effect on HIV-1 replication by targeting reverse transcriptase. Further study exhibited that 1 could block NNRTIs-resistant strains (HIV-1RT-K103N, HIV-1RT-L100I,K103N, HIV-1RT-K103N,V108I, HIV-1RT-K103N,G190A, and HIV-1RT-K103N,P225H) as well as wild-type HIV-1 (HIV-1wt) with EC50 values of 7.0, 23.8, 13.3, 14.2, 6.2, and 8.4 μM, respectively.

Phytochemical investigation on the whole plant of Chloranthus japonicus (Chloranthaceae) led to the isolation and identification of three new lindenane-type sesquiterpenoid dimers, chlorajaponilides F–H (1–3), along with seven known ones (4–10). Their chemical structures were established by extensive spectral evidence. Compounds 1 and 2 are both dimeric sesquiterpenoids featuring a rare hydroperoxy group at C-5. All compounds were tested for their activities on wild type HIV-1 replication and compounds 1, 2, 5, and 9 were effective with EC50 values from 3.08 to 17.16 μM. All these four compounds showed the same inhibitory effects on the two NNRTI-resistant HIV strains as on wild-type HIV-1 with EC50 change folds from 0.61 to 1.6 μM. Furthermore, compounds 1, 5, and 9 exhibited inhibitory activities on HCV replication with the similar potency as their activities on HIV-1. Our finding may provide a clue to address the problem of HIV-1 and HCV co-infection.Download high-res image (255KB)Download full-size image