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• Twenty-four new limonoids were obtained from Toona ciliata. • Their structures were determined by spectroscopic analysis, quantum chemistry calculations, and X-ray diffraction. • Several compounds showed significant anti-NLRP3 inflammasome activity. Twenty-four new limonoids, toonaolides A−X (1 – 24), characterized with an α , β -unsaturated- γ -lactone A-ring were isolated from the twigs of Toona ciliata. Their structures and absolute configurations were elucidated by spectroscopic data, X-ray diffraction crystallography, and quantum chemistry calculations. Most of the isolated compounds (except 9 , 18 , and 24 which possessed the maleimide ring) featured the rare 21-hydroxybutenolide or 23-hydroxybutenolide moieties. In particular, compound 1 has an unprecedented limonoid architecture with 6/6 cis -fused A/B ring system and 2 has an unusual tetrahydrofuran ring B skeleton, featuring a 7/5/6/5 ring system. The biological evaluation showed that compounds 9 , 11 , 12 , 14 , and 18 exhibited significantly anti-NLRP3 inflammasome activity with IC 50 values ranging from 3.2 to 9.7 μM. Analysis of IL-1 β and caspase-1 expression revealed that compounds 11 and 12 are selective inhibitors of NLRP3 inflammasome, which could ameliorate cell pyroptosis by blocking NLRP3 inflammasome activation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Seven new meroterpenoids and two new polyketides were isolated from the fungus Paraphaeosphaeria sp. C-XB-J-1. • Compounds 1 and 7 exhibited significant anti-inflammatory activity. • Compounds 4 and 7 showed potential inhibitory effects on the SARS-CoV-2 Mpro. Seven new meroterpenoids, paraphaeones A-G (1 – 7), and two new polyketides, paraphaeones H-I (8 – 9), along with eight known compounds (10 – 17), were isolated from the endophytic fungus Paraphaeosphaeria sp. C-XB-J-1. The structures of 1 – 9 were identified through the analysis of 1H, 13C, and 2D NMR spectra, assisted by HR-ESI-MS data. Compounds 1 and 7 exhibited a dose-dependent decrease in lactate dehydrogenase levels, with IC 50 values of 1.78 μM and 1.54 μM, respectively. Moreover, they inhibited the secretion of IL-1 β and CASP-1, resulting in a reduction in the activity levels of NLRP3 inflammasomes. Fluorescence microscopy results indicated that compound 7 concentration-dependently attenuated cell pyroptosis. Additionally, compounds 4 and 7 showed potential inhibitory effects on the severe acute respiratory syndrome coronavirus-2 main protease (SARS-CoV-2 Mpro), with IC 50 values of 10.8 ± 0.9 μM and 12.9 ± 0.7 μM, respectively. [ABSTRACT FROM AUTHOR]

[Display omitted] • Eleven new highly oxidized abietane diterpenoids were identified from Orthosiphon wulfenioides. • Compounds 1 – 4 , 6 and 8 exhibited potent inhibitory effects on NLRP3 inflammasome, and the IC 50 value of compound 1 was 0.23 μM. • Compound 1 inhibited cell pyroptosis via suppressing the expressions of Caspase-1 and IL-1β. Wulfenioidones A − K (1 – 11) were abietane diterpenoids with highly oxidized 6/6/6 aromatic tricyclic skeleton isolated from the whole plant of Orthosiphon wulfenioides , and their planar structures and absolute configurations were elucidated by spectroscopic data interpretation, electronic circular dichroism calculation as well as X-ray crystallography analysis. Bioactivity screening indicated that compounds 1 – 4 , 6 and 8 exhibited lactate dehydrogenase (LDH) inhibition effect with IC 50 values ranging from 0.23 to 3.43 μM by preventing the mononuclear macrophage cell pyroptosis induced by double signal stimulation of LPS and nigericin. Western Blot analyses of Caspase-1 and IL-1β down-regulation exhibited that compound 1 could selectively inhibit NLRP3 inflammasome, and the cell morphological observation further supported that compound 1 prevented macrophage cell pyroptosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Three unique ent -clerodane diterpenoid dimers were isolated from Callicarpa arborea. • The absolute configuration of 1 was deduced by single-crystal X-ray diffraction. • The absolute configuration of 2 and 3 was confirmed by NMR calculations with DP4 + analysis and ECD calculations. • The compound 2 and 3 showed potent cytotoxicity against MCF-7 and HCT-116 cell lines. Callicarpnoids A–C (1 – 3), three new ent -clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with IC 50 ranging from 5.2 to 7.2 μ M, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bcl 2 were decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • 66 ent -clerodane diterpenoids, including 52 new compounds, were isolated from Callicarpa arborea. • Their bioactivity against pyroptosis were evaluated, and the typical α,β-unsaturated-γ-hemiacetal lactone ring was a key active segments from SAR analysis. • Compound 1 showed potent inhibitory activity against pyroptosis by blocking NLRP3 inflammasome activation. • Compound 1 treatment markedly reduced infiltration of CD11b+F4/80+ macrophages into lung and protected lung injury in LPS- induced septic mice. Pyroptosis is a programmed-inflammatory cell death, which leads to release of inflammatory cellular contents and formation of inflammation. Uncontrollable pyroptosis can result in serious immune diseases, such as cytokine release syndrome (CRS), sepsis, disseminated intravascular coagulation (DIC), and acute organ damage, including acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Members of the Callicarpa genus are significant raw materials for traditional Chinese medicine, widely used for analgesia, hemostasis, and anti-inflammation. Previously, we have reported some ent -clerodane diterpenoids from Callicarpa arborea , shown potent inhibitory effects against pyroptosis. In this study, we went on investigating this kind of diterpenoids, and yielded 66 ent -clerodane diterpenoids, including 52 new compounds, from Callicarpa arborea. Their structures featured with a 5/6- (1 – 25) or a 6/6- (26 – 66)-fused double-ring scaffolds, were elucidated using spectroscopic data, electrostatic circular dichroism (ECD) and X-ray diffraction analyses. Screening for the inhibitory activity against pyroptosis by detecting of IL-1β secretion in J771A.1 cells, revealed 28 compounds with an IC 50 below 10.5 μM. Compound 1 was the most potent with an IC 50 of 0.68 μM and inhibited the J774A.1 macrophage pyroptosis by blocking the NLR pyrin domain containing 3 (NLRP3) inflammasome activation. An in vivo study further revealed that compound 1 decreased infiltration of CD11b + F4/80 + macrophages into lung and attenuated the lipopolysaccharide (LPS)-induced lung injury. Taken together, this study indicated the potential of compound 1 as a candidate for pyroptosis-related inflammation treatment, as well as provided the chemical and pharmacological basis for the further development of Callicarpa genus as a herbal medicine. [ABSTRACT FROM AUTHOR]

[Display omitted] • Nature-inspired compounds were found to inhibit HDAC and block inflammasome activation. • The active scaffold was discovered by virtual screening. • Derivatives of nigranoic acid and manwuweizic acid derivatives were prepared. As a successful anti-tumor drug target, the family of histone deacetylases (HDACs) is also a critical player in immune response, making the research of anti-inflammatory HDAC inhibitors an attractive new focus. In this report, triterpenoids nigranoic acid (NA) and manwuweizic acid (MA) were identified as HDAC inhibitors through docking-based virtual screening and enzymatic activity assay. A series of derivatives of NA and MA were synthesized and assessed for their biological effects. As a result, hydroxamic acid derivatives of NA and MA showed moderately increased activity for HDAC1/2/4/6 inhibition (the lowest IC 50 against HDAC1 is 1.14 μM), with no activity against HDAC8. In J774A.1 macrophage, compound 1 – 3 , 13 and 17 – 19 demonstrated inhibitory activity against lactate dehydrogenase (LDH) and IL-1β production, without affecting cell viability. Compound 19 increased the histone acetylation level in J774A.1 cells, as well as inhibited IL-1β maturation and caspase-1 cleavage. These results indicated that compound 19 blocks the activation of NLRP3 inflammasome, probably related to HDAC inhibition. This work provided a natural scaffold for developing low-cytotoxic and anti-inflammatory HDAC inhibitors, as well as a class of tool molecules for studying the relationship between HDACs and NLRP3 activation. [ABSTRACT FROM AUTHOR]

• A novel series of S -DABO derivatives have been designed and synthesized. • Selected compounds displayed potent activity against different HIV-1 strains. • Compound 5r only showed inhibition of HIV-1 DPDP activity unlike classical NNRTIs. • Preliminary SAR and molecular modeling of these novel congeners were investigated. In order to discover and develop the new HIV-1 NNRTIs, a series of 5-alkyl-6-(benzo[d][1,3]dioxol-5-ylalkyl)-2-mercaptopyrimidin-4(3H)-ones was synthesized and screened for their in vitro cytotoxicity against HIV-1. Most of the compounds we synthetized showed high activity against wild-type HIV-1 strain (IIIB) while IC 50 values are in the range of 0.06–12.95 μM. Among them, the most active HIV-1 inhibitor was compound 6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5b) , which exhibited similar HIV-1 inhibitory potency (IC 50 = 0.06 μM, CC 50 = 96.23 μM) compared with nevirapine (IC 50 = 0.04 μM, CC 50 >200 μM) and most of compounds exhibited submicromolar IC 50 values indicating they were specific RT inhibitors. The compounds 5b , 6-(benzo[d] [1,3]dioxol-5-yl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5c) and 4-(2-((4-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)acetyl)phenylbenzo[d][1,3]dioxole-5-carboxylate (5r) were selected for further study. It was found that all of them had little toxicity to peripheral blood mononuclear cell (PBMC), and had a good inhibitory effect on the replication of HIV-1 protease inhibitor resistant strains, fusion inhibitor resistant strains and nucleosides reverse transcriptase inhibitor resistant strains, as well as on clinical isolates. Besides, compound 5b and 5c showed inhibition of HIV-1 RT RNA-dependent DNA polymerization activity and DNA-dependent DNA polymerization activity, while compound 5r only showed inhibition of HIV DNA-dependent DNA polymerization activity, which was different from classical reverse transcriptase inhibitors. Our study which offered the preliminary structure-activity relationships and modeling studies of these new compounds has provided the valuable avenues for future molecular optimization. [ABSTRACT FROM AUTHOR]