α-Glucosidase Inhibitory Flavonoids and Oxepinones from the Leaf and Twig Extracts of Desmos cochinchinensis.

Four new flavonoids (1-4), a new benzyl benzoate derivative (5), five new oxepinones (6-10), and 14 known compounds (11-24) were isolated from the leaf and twig extracts of Desmos cochinchinensis. Their structures were established by spectroscopic methods. The structure of 1 was also confirmed by X-ray diffraction data. The absolute configurations of 3, 4, and 6-10 were determined from comparisons of their ECD spectra with those of relevant reported compounds. Compounds 1, 2, 6, 8, 10, 12-15, and 17 showed α-glucosidase inhibitory activities with IC50 values ranging from 0.2 to 4.9 µM.

Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs. To address the need for novel therapeutic options, we applied cell-based high-content screening to a library of natural products (NPs) obtained from plants, fungi, bacteria, and marine sponges, which represent a considerable diversity of chemical scaffolds. The antiviral effect of 373 NPs was evaluated using the mNeonGreen (mNG) reporter SARS-CoV-2 virus in a lung epithelial cell line (Calu-3). The screening identified 26 NPs with half-maximal effective concentrations (EC50) below 50 µM against mNG-SARS-CoV-2; 16 of these had EC50 values below 10 µM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC50 values in the nanomolar range. We demonstrated the pan-SARS-CoV-2 activity of these three lead antivirals against SARS-CoV-2 highly transmissible Omicron subvariants (BA.5, BA.2 and BA.1) and highly pathogenic Delta VOCs in human Calu-3 lung cells. Notably, holyrine A, alotaketal C, and bafilomycin D, are potent nanomolar inhibitors of SARS-CoV-2 Omicron subvariants BA.5 and BA.2. The pan-SARS-CoV-2 activity of alotaketal C [protein kinase C (PKC) activator] and bafilomycin D (V-ATPase inhibitor) suggest that these two NPs are acting as host-directed antivirals (HDAs). Future research should explore whether PKC regulation impacts human susceptibility to and the severity of SARS-CoV-2 infection, and it should confirm the important role of human V-ATPase in the VOC lifecycle. Interestingly, we observed a synergistic action of bafilomycin D and N-0385 (a highly potent inhibitor of human TMPRSS2 protease) against Omicron subvariant BA.2 in human Calu-3 lung cells, which suggests that these two highly potent HDAs are targeting two different mechanisms of SARS-CoV-2 entry. Overall, our study provides insight into the potential of NPs with highly diverse chemical structures as valuable inspirational starting points for developing pan-SARS-CoV-2 therapeutics and for unravelling potential host factors and pathways regulating SARS-CoV-2 VOC infection including emerging omicron BA.5 subvariants.

Isolation and crystal structure of lawinal.

The structure of the natural product lawinal [systematic name: (-)-(2S)-5,7-dihy-droxy-6-methyl-4-oxo-2-phenyl-chromane-8-carbaldehyde, C17H14O5] at 150 K is reported. The compound crystallizes with monoclinic (I2) symmetry and with Z' = 2. The absolute configuration could not be determined reliably from X-ray analysis only. However, our analysis returns the S-configuration at the C-2 position, consistent with previous stereochemical assignment from specific rotation. The independent mol-ecules form into alternating hydrogen-bonded chains with C-H⋯O=CH inter-molecular linkages that run parallel to the crystallographic a axis and are extended into the ac plane by π-π inter-actions between their phenyl substituents.

Antidiabetic and antimicrobial flavonoids from the twigs and roots of Erythrina subumbrans (Hassk.) Merr.

The phytochemical investigation of the twig and root extracts of Erythrina subumbrans (Hassk.) Merr. (Fabaceae) resulted in the isolation and identification of a new pterocarpan, erythrinocarpan (1), along with 27 known compounds (2-28). All isolated compounds were evaluated for their antidiabetic, antimicrobial, and anti-inflammatory properties. Compounds 3, 8, 9, and 22 had α-glucosidase inhibitory activity with IC50 values of 13.4 ± 0.05, 24.5 ± 0.13, 29.0 ± 0.05, and 12.8 ± 0.14 µM, respectively, while compound 2 inhibited α-amylase activity with an IC50 value of 67.6 ± 1.12 µM. Compounds 22 and 24 inhibited glycation activity with the IC50 values of 36.9 ± 0.62 and 40.5 ± 0.37 µM, respectively. From cell-based assays, compound 27 showed the highest ability to induce glucose consumption (IC50 29.1 ± 0.86 µM) and glucose uptake (2.8-fold), and to inhibit nitric oxide (NO) production (IC50 52.5 ± 0.56 µM) without cell toxicity. Furthermore, compound 9 showed antimicrobial activities against Gram-positive bacteria and fungi with MIC values ranging from 2-4 µg/mL.

Potent α-glucosidase inhibitory activity of compounds isolated from the leaf extracts of Uvaria hamiltonii.

The phytochemical investigation of the leaf extracts of Uvaria hamiltonii (Annonaceae) led to the isolation and identification of ten compounds including a new seco-cyclohexene (1) together with nine known compounds (2-10). Their structures were elucidated by intensive analysis by spectroscopic methods and comparisons of their spectroscopic data with those of compounds reported in the literature. Compounds 2, 8, and 9 showed potent α-glucosidase inhibitory activity with the IC50 values ranging from 2.6-7.1 µM.

Synthesis and crystal structure of (±)-Goniotamirenone C.

The structure of the racemic version of the natural product Goniotamirenone C [racemic anti-6-(2-chloro-1-hy-droxy-2-phenyl-eth-yl)-2H-pyran-2-one, C13H11ClO3] at 150 K is reported. The compound crystallizes with monoclinic (P21/n) symmetry and with Z' = 2. One independent mol-ecule is ordered while the other independent mol-ecule exhibits an inter-esting whole-mol-ecule enanti-omeric disorder with occupancies of 0.846 (4) and 0.154 (4). The independent mol-ecules are hydrogen bonded with -OH⋯O=C linkages into chains that run parallel to the a axis. This structural analysis corrects our previous assignment as the syn isomer [Meesakul et al. (2020 ▸). Phytochemistry, 171, 112248-112255].

Styryllactones from Goniothalamus tamirensis.

The phytochemical investigation of the twig and leaf extracts of Goniothalamus tamirensis led to the isolation and identification of 15 compounds including three rare previously undescribed styryllactones, goniotamirenones A-C, together with 12 known compounds. (Z)-6-Styryl-5,6-dihydro-2-pyranone and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one are reported here for the first time as previously undescribed natural products. Their structures were elucidated by spectroscopic methods. Goniotamirenone A was synthesized via a [2 + 2] cycloaddition reaction of 6-styrrylpyran-2-one in quantitative yield. The absolute configurations of goniotamirenones B and C were identified from experimental and calculated ECD data, while the absolute configurations of (-)-5-acetoxygoniothalamin, (-)-isoaltholactone, parvistone E, and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one were identified by single-crystal X-ray diffraction analysis using Cu Kα radiation. The absolute configurations of the other related compounds were determined from comparisons of their ECD spectra with relevant compounds reported in the literature. (-)-5-Acetoxygoniothalamin exhibited potent cytotoxicity against the colon cancer cell line (HCT116) with an IC50 value of 8.6 µM which was better than the standard control (doxorubicin, IC50 = 9.7 µM), while (Z)-6-styryl-5,6-dihydro-2-pyranone was less active with an IC50 value of 22.1 µM.

A New Cytotoxic Clerodane Diterpene from Casearia graveolens Twigs.

The first phytochemical investigation of Casearia graveolens twigs led to the isolation and identification of a new clerodane diterpene, caseariagraveolin (1), together with six known compounds (2-7). Their structures were elucidated by intensive analysis of their spectroscopic data. Compound 1 showed strong cytotoxicity against oral cavity and breast cancer cell lines with IC50 values of 2.48 and 6.63 µM, respectively.

Xanthones from Garcinia propinqua Roots.

Phytochemical investigation of Garcinia propinqua roots led to the isolation and identification of a new xanthone, doitunggarcinone D (1), together with 15 known compounds (2-16). Their structures were elucidated by intensive analysis of spectroscopic data. Compounds 3, 6, 7, 14, 15 and 16 exhibited strong antibacterial activity against Bacillus subtilis TISTR 088 with MIC values in the range of 1-4 µg/mL. Compounds 3, 7, 10 and 14 also showed good antibacterial activity against B. cereus TISTR 688 with MIC values ranging from 4-8 µg/mL.