Daphnane diterpenoid orthoesters with an odd-numbered aliphatic side chain from Daphne pedunculata.

Daphnane diterpenoids were recognized for their extensive range of potent biological activities. In the present study, phytochemical investigation including LC-MS/MS analysis resulted in the identification of five daphnane diterpenoid orthoesters (1-5). Among the five daphnane diterpenoids, two previously unreported compounds, daphnepedunins I and J (2 and 4) were isolated from Daphne pedunculata. The structure of new compounds was elucidated with extensive physicochemical and spectroscopic analyses. Their structure was characterized by the presence of an unusual odd-numbered aliphatic chain connected to an orthoester. The isolated compounds were evaluated for their anti-HIV activity against HIV-1 infection of MT4 cells, and the results indicated that compound 1 showed the most potent anti-HIV activity with an IC50 value of 0.82 nM.

Daphnepedunins G and H, anti-HIV macrocyclic 3,4-seco-daphnane orthoesters from Daphne pedunculata.

Daphnepedunins G (1) and H (2) with unusual macrocyclic 3,4-seco-daphnane orthoester structure were isolated from Daphne pedunculata. Their structures were determined by physicochemical and spectroscopic analyses combined with synthetic methods, including methyl esterification, derivatization reaction using a chiral anisotropic agent, and biomimetic conversion. Compounds 1 and 2 along with their methyl esters 1a and 2a were evaluated for anti-HIV activity, among which 1a and 2a exhibited potent activity with IC50 values of 1.08 and 1.17 µM, respectively.

LC-MS identification, isolation, and structural elucidation of anti-HIV macrocyclic daphnane orthoesters from Edgeworthia chrysantha.

The occurrence of macrocyclic daphnane orthoesters (MDOs) with a 1-alkyl group originating from a C14 aliphatic chain is extremely limited in the plant kingdom and has only been isolated from Edgeworthia chrysantha. In the present study, LC-ESI-MS/MS analysis was performed on different parts of E. chrysantha, including flower buds, flowers, leaves, and stems, and resulted in the identification of seven MDOs in all the four plant parts, including two previously unreported compounds 1 and 7. Further LC-MS guided isolation was carried out to afford compounds 1 and 7, and their structures were determined by various spectroscopic analyses. These compounds were also evaluated for anti-HIV activity, thus expanding insights into the structure-activity relationships for MDOs.

Discovery of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles as potent HIV-1 NNRTIs with improved anti-resistance and drug-like profiles.

Taking our previously reported HIV-1 NNRTIs BH-11c and XJ-10c as lead compounds, series of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles were designed to improve anti-resistance and drug-like profiles. According to the three rounds of in vitro antiviral activity screening, compound 12g was the most active inhibitor against wild-type and five prevalent NNRTI-resistant HIV-1 strains with EC50 values ranging from 0.024 to 0.0010 µM. This is obviously better than the lead compound BH-11c and the approved drug ETR. Detailed structure-activity relationship was investigated to provide valuable guidance for further optimization. The MD simulation study indicated that 12g could form additional interactions with residues around the binding site in HIV-1 RT, which provided reasonable explanations for its improved anti-resistance profile compared to ETR. Furthermore, 12g showed significant improvement in water solubility and other drug-like properties compared to ETR. The CYP enzymatic inhibitory assay indicated that 12g was unlikely to induce CYP-mediated drug-drug interactions. 12g pharmacokinetics parameters were investigated and it displayed a long half-life of 6.59 h in vivo. The properties of compound 12g make it a promising lead compound for the development of new generation of antiretroviral drugs.

Anti-HIV Potential of Beesioside I Derivatives as Maturation Inhibitors: Synthesis, 3D-QSAR, Molecular Docking and Molecular Dynamics Simulations.

HIV-1 maturation is the final step in the retroviral lifecycle that is regulated by the proteolytic cleavage of the Gag precursor protein. As a first-in-class HIV-1 maturation inhibitor (MI), bevirimat blocks virion maturation by disrupting capsid-spacer peptide 1 (CA-SP1) cleavage, which acts as the target of MIs. Previous alterations of beesioside I (1) produced (20S,24S)-15ꞵ,16ꞵ-diacetoxy-18,24; 20,24-diepoxy-9,19-cyclolanostane-3ꞵ,25-diol 3-O-3',3'-dimethylsuccinate (3, DSC), showing similar anti-HIV potency compared to bevirimat. To ascertain the binding modes of this derivative, further modification of compound 1 was conducted. Three-dimensional quantitative structure−activity relationship (3D-QSAR) analysis combined with docking simulations and molecular dynamics (MD) were conducted. Five new derivatives were synthesized, among which compound 3b showed significant activity against HIV-1NL4-3 with an EC50 value of 0.28 µM. The developed 3D-QSAR model resulted in great predictive ability with training set (r2 = 0.99, q2 = 0.55). Molecular docking studies were complementary to the 3D-QSAR analysis, showing that DSC was differently bound to CA-SP1 with higher affinity than that of bevirimat. MD studies revealed that the complex of the ligand and the protein was stable, with root mean square deviation (RMSD) values <2.5 Å. The above results provided valuable insights into the potential of DSC as a prototype to develop new antiviral agents.

Daphnepedunins A-F, Anti-HIV Macrocyclic Daphnane Orthoester Diterpenoids from Daphne pedunculata.

From the whole plant of Daphne pedunculata, 12 macrocyclic daphnane diterpenoids, including six new compounds, daphnepedunins A-F (1-4, 9, and 10), were isolated. Their structures were elucidated by physiochemical and spectroscopic data analysis, the modified Mosher's method, and X-ray crystallography. The isolated compounds were evaluated for anti-HIV activity against HIV-1 infection in MT4 cells and showed significant anti-HIV activity with IC50 values of 36.3-994 nM. A consideration of the anti-HIV activity of these compounds provided further insight into the structure-activity relationships of macrocyclic daphnane diterpenoids.

Tigliane-Type Diterpene Esters from the Fruits of Shirakiopsis indica and Their Anti-HIV Activity.

Four new diterpene esters, shirakindicans A-D (1-4), along with eight related known diterpene esters (5-12), were isolated from the fruits of the Bangladeshi medicinal plant Shirakiopsis indica. The structures of 1-4 were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Shirakindican A (1) was assigned as a tigliane-type diterpene ester possessing an unusual 6ß-hydroxy-1,7-dien-3-one structure, while shirakindican B (2) exhibits a tiglia-1,5-dien-3,7-dione structure. The anti-HIV activities of the isolated diterpene esters were evaluated and showed significant activities for sapintoxins A (5) and D (11), with EC50 values of 0.0074 and 0.044 µM, respectively, and TI values of 1 100 and 5 290. Sapatoxin A (12) also exhibited anti-HIV activity with an EC50 value of 0.13 µM and a TI value of 161.

Quinolizidines as Novel SARS-CoV-2 Entry Inhibitors.

COVID-19, caused by the highly transmissible severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has rapidly spread and become a pandemic since its outbreak in 2019. We have previously discovered that aloperine is a new privileged scaffold that can be modified to become a specific antiviral compound with markedly improved potency against different viruses, such as the influenza virus. In this study, we have identified a collection of aloperine derivatives that can inhibit the entry of SARS-CoV-2 into host cells. Compound 5 is the most potent tested aloperine derivative that inhibited the entry of SARS-CoV-2 (D614G variant) spike protein-pseudotyped virus with an IC50 of 0.5 µM. The compound was also active against several other SARS-CoV-2 variants including Delta and Omicron. Results of a confocal microscopy study suggest that compound 5 inhibited the viral entry before fusion to the cell or endosomal membrane. The results are consistent with the notion that aloperine is a privileged scaffold that can be used to develop potent anti-SARS-CoV-2 entry inhibitors.

Anti-HIV Macrocyclic Daphnane Orthoesters with an Unusual Macrocyclic Ring from Edgeworthia chrysantha.

Edgeworthianins A-E (1-5) were isolated from Edgeworthia chrysantha as a class of macrocyclic daphnane orthoesters with an unusual macrocyclic ring formed from a C14 aliphatic chain. Their structures were elucidated by extensive physicochemical and spectroscopic analyses. Compounds 2, 4, and 5 exhibited potent anti-HIV activity against HIV-1 infection of MT4 cells with EC50 values of 29.3, 8.4, and 2.9 nM, respectively. These compounds broaden the findings of the structure-activity relationship of macrocyclic daphnane orthoesters for further anti-HIV drug development.

Anti-HIV Tigliane-Type Diterpenoids from the Aerial Parts of Wikstroemia lichiangensis.

Tigliane-type diterpenoids have attracted much attention in drug discovery since they have been reported to exhibit remarkable biological effects, such as tumor-promoting, antineoplastic, and anti-HIV activities. In continuing our efforts to discover novel biologically important diterpenoids from Wikstroemia species, Wikstroemia lichiangensis was investigated phytochemically for the first time. As a result, four new (1-4) and one known (5) tigliane-type diterpenoid were isolated, and their structures were elucidated by spectroscopic data analysis. Tiglianes (1-5) showed potent anti-HIV activity against HIV-1 infection of MT4 lymphocytes with IC50 values of 1.1-65.4 nM.

Iridoids and sesquiterpenoids from Valeriana jatamansi and their anti-influenza virus activities.

Twenty-one new iridoids, jatamansidoids A-U (1-12, 21-26, 32, 35 and 36), two new natural ones, jatamansidoids V (37) and W (38), eighteen known ones (13-20, 27-31, 33 and 34), together with three patchoulol-type sesquiterpenoids (39-41), were isolated from the roots and rhizomes of Valeriana jatamansi. Structurally, compounds 1-7 were the first examples of iridoids from V. jatamansi with unique α, ß, γ, δ-unsaturated aldehyde fragment between C-11, C-4, C-5, C-9 and C-8; compound 8 was an unprecedented iridoid derivative with a methyl group (Me-10) at C-1, rather than C-8, and its plausible biogenetic pathway was proposed in this paper; compounds 22 and 23 were the first examples of Δ4(5)-iridoids simultaneously replaced by oxygen-containing groups at C-3, C-6 and C-7; compound 24 was the first iridoid with both 6,7- and 1,10-epoxy fragments. The structures and absolute configurations of new compounds were elucidated based on extensive spectroscopic techniques and quantum chemical calculation. Furthermore, compounds 13-15 and 39-41 exhibited potent anti-influenza virus activities with H1N1 and H3N2 strains, with IC50 values of 0.21-1.48 µM.

Experience in different modes of delivery in twin pregnancy.

BACKGROUND/PURPOSE: Vaginal delivery, compared with Cesarean delivery, remains a less chosen mode of delivery for twin pregnancy. We studied the maternal and perinatal outcomes of twin pregnancy with different modes of delivery. METHODS: A retrospective study with data collected from a regional hospital, including vital twin pregnancies delivered at gestational age of 32 weeks and above. Medical charts were reviewed for prenatal conditions and postpartum outcomes. RESULTS: Ninety-eight pairs of twins were included and 44.9% were delivered via vaginal delivery. Women in the vaginal delivery group were significantly younger (32.5 ±4.3 years versus 34.8 ±4.6 years, p < 0.01), multiparous (34.1% versus 18.5%) and with more twins in vertex-vertex presentation (70.5% versus 33.3%) compared with women in the Cesarean delivery group. There were no differences between maternal postpartum complications and neonatal outcomes in both groups. The outcomes showed longer inter-twin delivery time interval (5.7 ± 5.6 versus 1.5 ± 0.9 min, p < 0.01), less estimated blood loss (198.7 ± 144.1 versus 763.2 ± 332.3 mL, p < 0.01), and shorter maternal hospital stay (3.0 ± 0.5 versus 5.7 ± 0.5 days, p< 0.01) in the vaginal delivery group. Twenty newborns had Apgar score below seven at birth. Logistic regression analysis revealed that low Apgar score was independently related to younger maternal age, maternal obstetric diseases and fetal non-vertex presentation. Gestational weeks and mode of delivery were not related to low Apgar score. CONCLUSION: With careful case selection, vaginal delivery could be safely performed in twin pregnancies with less estimated blood loss and better recovery than Cesarean delivery.

Design, synthesis, and antiviral activity of phenylalanine derivatives as HIV-1 capsid inhibitors.

The HIV-1 Capsid (CA) is considered as a promising target for the development of potent antiviral drugs, due to its multiple roles during the viral life cycle. Herein, we report the design, synthesis, and antiviral activity evaluation of series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors. Among them, 4-methoxy-N-methylaniline substituted phenylalanine (II-13c) and indolin-5-amine substituted phenylalanine (V-25i) displayed exceptional anti-HIV-1 activity with the EC50 value of 5.14 and 2.57 µM respectively, which is slightly weaker than that of lead compound PF-74 (EC50 = 0.42 µM). Besides, surface plasmon resonance (SPR) binding assay demonstrated II-13c and V-25i prefer to combine with CA hexamer rather than monomer, which is similar to PF-74. Subsequently, molecular dynamics simulation (MD) revealed potential interactions between representative compounds with HIV-1 CA hexamer. Overall, this work laid a solid foundation for further structural optimization to discover novel promising HIV-1 CA inhibitors.

LC-MS Identification, Isolation, and Structural Elucidation of Anti-HIV Tigliane Diterpenoids from Wikstroemia lamatsoensis.

Structurally diverse tigliane diterpenoids have drawn significant research interest for drug discovery over many decades. Using LC-MS-guided fractionation and separation, the first phytochemical investigation on Wikstroemia lamatsoensis led to the isolation of eight tiglianes (1-8), including two new compounds, wikstrocin D (1) and wikstrocin E (2). The new structures were elucidated based on extensive physicochemical and spectroscopic analyses. The characteristic ESIMS/MS fragmentations of tiglianes 1-8 were also summarized. Among the isolated tiglianes, three compounds (8, 5, and 7) showed the most potent anti-HIV activity, with IC50 values of 0.18, 3.8, and 12.8 nM, respectively.

New phorbol ester derivatives as potent anti-HIV agents.

Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.

Identification of anti-HIV macrocyclic daphnane orthoesters from Wikstroemia ligustrina by LC-MS analysis and phytochemical investigation.

Macrocyclic daphnane orthoesters (MDOs) have attracted significant research interest for the drug discovery to cure HIV infection based on the "Shock and Kill" strategy. In the present study, the first chemical study on Wikstroemia ligustrina (Thymelaeaceae) was carried out by LC-MS analysis and phytochemical investigation. Nine daphnane diterpenoids (1-9) including seven MDOs were detected by LC-MS analysis. Further phytochemical investigation resulted in the isolation and structural elucidation of five daphnanes (1, 2, 5, 8, and 9) with potent anti-HIV activity. Taking the isolated MDO (1) as a model compound, the MS/MS fragmentation pathway was also elucidated.

Hyperdioxanes, dibenzo-1,4-dioxane derivatives from the roots of Hypericum ascyron.

Six dibenzo-1,4-dioxane derivatives (1-6) were isolated from the roots of a Hypericaceous plant Hypericum ascyron. Spectroscopic analyses revealed 2 and 4-6 to be new compounds. The partial racemic natures of 1-3 were concluded by chiral HPLC analyses, while 5 was confirmed to be a racemate. The absolute configurations 1-4 were deduced on the basis of ECD calculations. Biological activity evaluation of the dibenzo-1,4-dioxane derivatives along with two related compounds: hyperdioxanes A (7) and B (8), previously isolated from the same plant material by our group demonstrated that 7 exhibit an anti-HIV activity (IC50 5.3 µM, TI 7.2) while 8 showed an inhibitory effect on IL-1ß production (inhibition rate: 72.3% at 6.3 µM) from LPS-stimulated microglial cells.

Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors.

Prior modification of betulinic acid (1), a natural product lead with promising anti-HIV activity, produced 3-O-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat, 3), the first-in-class HIV maturation inhibitor. After 3-resistant variants were found during Phase I and IIa clinical trials, further modification of 3 produced 4 with improved activity against wild-type and 3-resistant HIV-1. In continued efforts to optimize 1, 63 final products have now been designed, synthesized, and evaluated for anti-HIV-1 replication activity against HIV-1NL4-3 infected MT-4 cell lines. Five known and 21 new derivatives were as or more potent than 3 (EC50 0.065 µM), while eight new derivatives were as or more potent than 4 (EC50 0.019 µM). These derivatives feature expanded structural diversity and chemical space that may improve the antiviral activity and address the growing resistance crisis. Structure-Activity Relationship (SAR) correlations were thoroughly analyzed, and a 3D Quantitative SAR model with high predictability was constructed to facilitate further rational design and development of new potent derivatives.

Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.

Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti-HIV potency in TZM-bl and MT-4 cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC50 values ranging from 2.45 nM to 5.36 nM, and 14c (EC50 = 2.45 nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC50 = 10.6 nM), being comparable with ETR (EC50 = 9.80 nM) and 3.5-fold more potent than that of compound 7 (EC50 = 37.3 nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC50 = 0.0589 µM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by molecular dynamics simulation. Overall, we envision that the "dual-site"-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti-HIV-1 agents.

Design and Synthesis of Quinolizidine Derivatives as Influenza Virus and HIV-1 Inhibitors.

BACKGROUND: We have previously reported that a quinolizidine natural product, aloperine, and its analogs can inhibit influenza virus and/or HIV-1 at low µM concentrations. OBJECTIVE: The main goal of this study was to further optimize aloperine for improved anti-influenza virus activity. METHODS: Structural modifications have been focused on the N12 position of aloperine scaffold. Conventional chemical synthesis was used to obtain derivatives with improved antiviral activities. The anti-HIV and anti-influenza virus activities of the synthesized compounds were determined using an MT4 cell-based HIV-1 replication assay and an anti- influenza virus infection of MDCK cell assay, respectively. RESULTS: Aloperine derivatives can be classified into three activity groups: those that exhibit anti-HIV activity only, anti-influenza virus only, or activity against both viruses. Aloperine optimized for potent anti-influenza activity often lost anti-HIV-1 activity, and vice versa. Compound 19 inhibited influenza virus PR8 replication with an IC50 of 0.091 µM, which is approximately 160- and 60-fold more potent than aloperine and the previously reported aloperine derivative compound 3, respectively. CONCLUSION: The data suggest that aloperine is a privileged scaffold that can be modified to become a selective antiviral compound with markedly improved potency against influenza virus or HIV-1.