Utilizing artificial intelligence for precision exploration of N protein targeting phenanthridine sars-cov-2 inhibitors: A novel approach.

The persistent mutation of the novel coronavirus presents a continual threat of infections and associated illnesses. While considerable research efforts have concentrated on the functional proteins of SARS-CoV-2 in the development of anti-COVID-19 therapeutics, the structural proteins, particularly the N protein, have received comparatively less attention. This study focuses on the N protein, a critical structural component of the virus, and employs advanced deep learning models, including EMPIRE and DeepFrag, to optimize the structures of phenanthridine-based compounds. More than 10,000 small molecules, derived through deep learning, underwent high-throughput virtual screening, resulting in the synthesis of 44 compounds. Compound 38 showed a binding potential energy of -8.2 kcal/mol in molecular docking. Surface Plasmon Resonance (SPR) and Microscale Thermophoresis (MST) validation yielded dissociation constants of 353 nM and 726 nM, confirming strong binding to the N protein. Compound 38 demonstrated antiviral activity in vitro and exhibited anti-COVID-19 effects by interfering with the binding of N proteins to RNA. This research underscores the potential of targeting the SARS-CoV-2 N protein for therapeutic intervention and illustrates the efficacy of deep learning model in the design of lead compounds. The application of these deep learning models represents a promising approach for accelerating the discovery and development of antiviral agents.

Diterpenoids target SARS-CoV-2 RdRp from the roots of Euphorbia fischeriana Steud.

Introduction: Currently, the development of new antiviral drugs against COVID-19 remains of significant importance. In traditional Chinese medicine, the herb Euphorbia fischeriana Steud is often used for antiviral treatment, yet its therapeutic effect against the COVID-19 has been scarcely studied. Therefore, this study focuses on the roots of E. fischeriana Steud, exploring its chemical composition, antiviral activity against COVID-19, and the underlying basis of its antiviral activity. Methods: Isolation and purification of phytochemicals from E. fischeriana Steud. The elucidation of their configurations was achieved through a comprehensive suite of 1D and 2D NMR spectroscopic analyses as well as X-ray diffraction. Performed cytopathic effect assays of SARS-CoV-2 using Vero E6 cells. Used molecular docking to screen for small molecule ligands with binding to SARS-CoV-2 RdRp. Microscale thermophoresis (MST) was used to determine the dissociation constant Kd. Results: Ultimately, nine new ent-atisane-type diterpenoid compounds were isolated from E. fischeriana Steud, named Eupfisenoids A-I (compounds 1-9). The compound of 1 was established as a C-19-degraded ent-atisane-type diterpenoid. During the evaluation of these compounds for their antiviral activity against COVID-19, compound 1 exhibited significant antiviral activity. Furthermore, with the aid of computer virtual screening and microscale thermophoresis (MST) technology, it was found that this compound could directly bind to the RNA-dependent RNA polymerase (RdRp, NSP12) of the COVID-19, a key enzyme in virus replication. This suggests that the compound inhibits virus replication by targeting RdRp. Discussion: Through this research, not only has our understanding of the antiviral components and material basis of E. fischeriana Steud been enriched, but also the potential of atisane-type diterpenoid compounds as antiviral agents against COVID-19 has been discovered. The findings mentioned above will provide valuable insights for the development of drugs against COVID-19.

Potential SARS-CoV-2 Mpro steroid inhibitors from Aphanamixis polystachya (Wall.) R. N. Parker.

Herein, six previously undescribed steroids (1-6), were isolated from leaves and twigs of Aphanamixis polystachya (Wall.) R. N. Parker (Meliaceae). Their structures were elucidated by comprehensive spectroscopic analysis, including HRESIMS, 1D and 2D NMR, UV, and IR. Antiviral activity of these compounds were evaluated. Compounds 1-6 showed varying degrees of inhibitory activity against the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro) at 200 µM.

Daphmacrimines A-K, Daphniphyllum alkaloids from Daphniphyllum macropodum Miq.

Daphmacrimines A-K (1-11) were isolated from the leaves and stems of Daphniphyllum macropodum Miq. Their structures and stereochemistries were determined by extensive techniques, including HRESIMS, NMR, ECD, IR, and single-crystal X-ray crystallography. Daphmacrimines A-D (1-4) are unprecedented Daphniphyllum alkaloids with a 2-oxazolidinone ring. Daphmacrimine I (9) contains a nitrile group, which is relatively rare in naturally occurring alkaloids. The abilities of daphmacrimines A-D and daphmacrimines G-K to enhance lysosomal biogenesis were evaluated through LysoTracker Red staining. Daphmacrimine K (11) can induce lysosomal biogenesis and promote autophagic flux.

Five new limonoids isolated from Walsura robusta.

Five new toosendanin limonoids with highly oxidative furan ring walsurobustones A-D (1-4), and one new furan ring degraded limonoid walsurobustone E (5) together with one known compound toonapubesic acid B (6) were isolated from the leaves of Walsura robusta. Their structures were elucidated by NMR and MS data. Especially, the absolute configuration of toonapubesic acid B (6) was confirmed by X-ray diffraction study. Compounds 1-6 exhibited good cytotoxicity against the cancer cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480.

Novel nucleocapsid protein-targeting phenanthridine inhibitors of SARS-CoV-2.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented in human history. As a major structural protein, nucleocapsid protein (NPro) is critical to the replication of SARS-CoV-2. In this work, 17 NPro-targeting phenanthridine derivatives were rationally designed and synthesized, based on the crystal structure of NPro. Most of these compounds can interact with SARS-CoV-2 NPro tightly and inhibit the replication of SARS-CoV-2 in vitro. Compounds 12 and 16 exhibited the most potent anti-viral activities with 50% effective concentration values of 3.69 and 2.18 µM, respectively. Furthermore, site-directed mutagenesis of NPro and Surface Plasmon Resonance (SPR) assays revealed that 12 and 16 target N-terminal domain (NTD) of NPro by binding to Tyr109. This work found two potent anti-SARS-CoV-2 bioactive compounds and also indicated that SARS-CoV-2 NPro-NTD can be a target for new anti-virus agents.

Two new cytotoxic cycloartane triterpenoids from Aphanamixis polystachya (Wall.) R. N. Parker.

Two new cycloartane triterpenoids, (24 R)-cycloartane-3ß,24,25,30-tetrol (1) and (24 R)-24,25,30-trihydroxy-9,19-cycloartane-3-one (2), along with three known compounds (3-5) were isolated from leaves and twigs of Aphanamixis polystachya. The new compounds were elucidated based on comprehensive spectroscopic analysis, including 1 D, 2 D NMR and HREIMS. The in vitro cytotoxic activities evaluation of five human cancer cell lines revealed that compound 1 exhibited cytotoxic activity on all of tested human cancer cell lines, while compound 2 only had specific activity on SMMC-7721 cell line.

Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new anti-vitiligo compounds.

Humans have been suffering from vitiligo for a long time. Target vitiligo drugs have yet been approved. Activation of Wnt/ß-catenin signalling has potential in the therapeutic use of vitiligo, so exploring new drugs that specifically directly activate Wnt is worthwhile to obtain new anti-vitiligo agents. In this work, two portions design and synthesis were put into effect. firstly, 17 phenanthridine derivatives with C-4 substitutes were designed and synthesized, which compounds 4, 6, 12, 13 served as H-acceptor with protein showed enhance melanogenesis activity; Secondly, 7 hybrid new scaffolds of compounds were designed and synthesized, scaffold hopping compound 36 that aromatic benzene was replaced pyrazole on ring C showed enhance melanogenesis and tyrosinase activity; The last and most important, a comprehensive optimization and SARs of compound 36 were carried out, compounds 41 and 43 shared phenolic hydroxyl or 3-methyl-pyridine substitutes at C-7 position remarkably improved the capacity of melanogenesis and tyrosinase activity. Compound 43 were identified as new anti-vitiligo agents that specifically activate the Wnt/ß-catenin signalling pathway by targeting Axin. Structure-activity relationship analysis implied that H-acceptor substitutions at the C-4 position and phenolic hydroxyl or pyridine substitutions at the C-7 position would improve the activities of the compounds. These findings reveal a new therapeutic strategy for vitiligo, and compounds 41 and 43 may represent potential compounds for vitiligo treatment.

Phenanthridine Derivative Host Heat Shock Cognate 70 Down-Regulators as Porcine Epidemic Diarrhea Virus Inhibitors.

Porcine epidemic diarrhea virus (PEDV) has become increasingly problematic around the world, not only for its hazards to livestock but also due to the possibility that it is a zoonotic disease. Although vaccine therapy has made some progress toward PEDV control, additional effective therapeutic strategies against PEDV are needed, such as the development of chemotherapeutic agents. The aim of this work was to identify novel anti-PEDV agents by designing and synthesizing a series of phenanthridine derivatives. Among them, three compounds (compounds 1, 2, and 4) were identified as potent anti-PEDV agents exhibiting suppression of host cell heat shock cognate 70 (Hsc70) expression. Mechanism studies revealed that host Hsc70 is involved in the replication of PEDV, and its expression can be suppressed by destabilization of the mRNA, resulting in inhibition of PEDV replication. Activity against PEDV in vivo in PEDV-infected piglets suggested that phenanthridine derivatives are the first host-acting potential anti-PEDV agents.

Aphananoid A is an Anti-Inflammatory Limonoid with a New 5/6/5 Fused Ring Featuring a C24 Carbon Skeleton from Aphanamixis polystachya.

Aphananoid A, a limonoid which features a rare C24 appendage and new 5/6/5 fused-ring framework, was obtained from Aphanamixis polystachya. The planar structure as well as the absolute configuration was identified based on extensive spectroscopic analysis and electronic circular dichroism calculations. The biogenetic pathway of aphananoid A was also speculated, which arises from the triterpene by the 3,4-seco-7,8-seco-6,8 cyclo-7,30-decarbon key pattern. In addition, bioassays indicated that aphananoid A inhibited NO production in the RAW264.7 cell line (46.80 ± 1.93%).

Diterpenes with potential treatment of vitiligo from the aerials parts of Euphorbia antiquorum L.

Six new diterpenes Euphonoids A-F including one ingenol (1), three lathyrane (2-5), one ent-abietane (6) and fifteen known derivatives (7-21) were isolated from the aerial parts of Euphorbia antiquorum L. Their structures were elucidated by physical data analysis. Compounds 1, 12, and 16 improve the melanogenesis in B16 cells in vitro.

Two new bioactive lignans from leaves and twigs of Cleistanthus concinnus Croizat.

Two new lignans (1-2), along with five known compounds (3-7) with different structures were isolated from leaves and twigs of Cleistanthus concinnus Croizat. The new lignans were elucidated as (7'R,8'S)-3,3',5'-trimethoxy-4,4'-dihydroxy-7-en-7',9- epoxy-8,8'-lignan (1) and (7'R,8'S)-3,3'-dimethoxy-4,4'-dihydroxy-7-en-7',9-epoxy-8, 8'-lignan (2) by comprehensive spectroscopic analysis including 1D and 2D NMR as well as HREIMS and comparing their NMR data with known compounds in the literature. Among these isolated compounds, compound 1, 2, 3, and 6 were tested for anti- inflammatory effects by inhibiting NO production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Compound 1, 2, and 6 exhibit NO inhibitory activity.[Formula: see text].

Stelleraguaianone B and C, two new sesquiterpenoids from Stellera chamaejasme L.

Two new sesquiterpenoids were isolated from Stellera chamaejasme L., known as the traditional Chinese herb 'Rui Xiang Lang Du'. The compounds were elucidated as stelleraguaianone B (1) and C (2) by comprehensive spectroscopic analysis, including 1D and 2D NMR as well as HRESIMS, and by comparing their NMR data with known compounds. In addition, the structure of 1 was further confirmed by single-crystal X-ray diffraction analysis. Both the compounds were evaluated for their cytotoxicity on common tumour cell lines in vitro, which revealed that compound 1 exhibits cytotoxic activity on A549 cells, while 2 has no activity.

Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/ß-catenin signalling pathway agonists.

Phenanthridine derivativeHLY78 has previously been identified as the first Wnt/ß-catenin signalling pathway agonist that targets the DAX domain of axin. However, due to the relatively weak activation on the Wnt/ß-catenin signalling pathway, HLY78 is insufficient for further pharmacological study. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships (SARs) of HLY78-derived phenanthridine derivatives as agonists of the Wnt/ß-catenin signalling pathway are presented. In this work, 36 derivatives were designed and synthesized with some derivatives exhibiting stronger Wnt activity than the activity of HLY78. In particular, one of them, 8-((1,3-dimethy-pyrazol-5-yl)methoxy)-5-ethyl-4-methyl-5,6-dihydro-phenanthridin-9-ol, exhibited strong Wnt active activity and is 10 times more potent than HLY78. The following SAR analysis suggests that a pyrazole group, especially at the C-8 position, is important for Wnt activation; a methyl group at the C-4position seems to be more beneficial for Wnt activation than ethyl; and oxidation of the C-6 position reduces the Wnt activation.

An Explorer of Chemical Biology of Plant Natural Products in Southwest China, Xiaojiang Hao.

Xiaojiang Hao, who obtained Master Degree from Kunming Institute of Botany (KIB), Chinese Academy of Sciences (CAS) in 1985, and Doctor in Pharmacy degree in Pharmacy from Institute for Chemical Research, Kyoto University, in 1990, was born in Chongqing in July, 1951. In 1991, he returned to KIB, CAS, as an Associate professor and served as the chair of the Department of Phytochemistry. In 1994, he was promoted to a full professor at the current institute. He served as the Deputy Director of KIB and the Director of Open Laboratory of Phytochemistry from 1995 to 1997, and the Director of KIB from 1997 to 2005. Professor Hao has published more than 450 peer-reviewed SCI papers, which have been cited over 6000 times. He has obtained one PCT patent and 23 patents in China. Due to his tremendous efforts, one candidate drug, phenchlobenpyrrone, has entered the Phase II clinical trail for the treatment of Alzheimer's disease. Moreover, he won the First Prize of Natural Sciences in Yunnan Province for three times, and Ho Leung Ho Lee Fund Science and Technology Innovation Award in 2017.

Cytotoxic indole alkaloids from Melodinus khasianus and Melodinus tenuicaudatus.

Four new indole alkaloids, melodinusines A-D (1, 2, 6, and 7), along with 26 known indole alkaloids, were isolated from Melodinus tenuicaudatus and Melodinus khasianus (Melodinus genus). Among them, 1 and 2 are aspidospermine-aspidospermine-type bisindole alkaloids while 7 is a novel melodinus-type alkaloid. Their structures were established on the basis of comprehensive spectroscopic data analysis and the structure of 7 was further confirmed by single-crystal X-ray diffraction analysis. Their cytotoxic activities against five human cancer cell lines, HL-60, SMMC-7721, A-549, MCF-7, and SW480 were also evaluated.

Anti-TMV Effects of Amaryllidaceae Alkaloids Isolated from the Bulbs of Lycoris radiata and Lycoricidine Derivatives.

Fifteen known amaryllidaceae alkaloids were isolated from the bulbs of Lycoris radiata. Some of the compounds and lycoricidine derivatives had been screened for the activities against tobacco mosaic virus (TMV) by the conventional half-leaf method. Lycoricidine derivatives were also carried out the assay of effect on systemic infection of TMV by western-blot and RT-PCR analysis. The tested compounds showed moderate inactivation effect, whereas the lycoricidine derivatives showed good protective effect. The protective inhibitory activity of compounds L1 (N-methyl-2,3,4-trimethoxylycoricidine) (60.8%) and L3 (N-methyl-2-methoxy-3,4-acetonidelycoricidine) (62.0%) was almost similar to the positive control, Ningnanmycin (66.4%). RT-PCR and Western-blot analysis displayed that compounds L1, L3, L5 (N-allyl-2,3,4-triallyloxylycoricidine) exhibited antiviral activity, which was evidenced by reducing TMV-CP gene replication and TMV-CP protein expression. Additionally, defensive enzyme activities confirmed that compound L1 could increase the activity of PAL, POD, SOD to improve disease resistance of tobacco.

Hypermonins A and B, two 6-norpolyprenylated acylphloroglucinols with unprecedented skeletons from Hypericum monogynum.

Two new 6-norpolycyclic polyprenylated acylphloroglucinols (PPAPs), hypermonins A (1) and B (2), featuring an undescribed decahydroindeno[1,7-bc]furan ring system, were isolated from the leaves and twigs of Hypericum monogynum. These compounds are a pair of epimers with opposite configurations at the C-5 position. Their structures, including their absolute configurations, were determined by extensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. A plausible biosynthetic pathway of 1 and 2 was also proposed. Compound 1 exhibited a significant protective effect against corticosterone-induced injury in PC12 cells.

Two novel diterpenoid heterodimers, Bisebracteolasins A and B, from Euphorbia ebracteolata Hayata, and the cancer chemotherapeutic potential of Bisebracteolasin A.

Rare ent-abietane-rosane diterpenoid heterodimers, Bisebracteolasins A and B (1 and 2, respectively), were isolated from the roots of Euphorbia ebracteolata Hayata. Their structures and absolute configurations were elucidated from spectroscopic data and X-ray diffraction analysis. Compounds 1 and 2 exhibited moderate cytotoxic effects against five cancer cell lines. Compound 1 showed more effective antiproliferative activities against human tumour cells, HL-60 and SMMC-7721, with IC50 values of 2.61 and 4.08 µM, respectively, than 2. Both compounds 1 and 2 inhibit the colorectal cancer stem cell line P6C with IC50 values of 16.48 and 34.76 µM, respectively. Moreover, preliminary biological tests showed compound 1 exhibited inhibitory activity towards tumoursphere formation and migration of the P6C cell line. Overall, we identified two novel diterpenoid heterodimers, and Bisebracteolasin A exhibits therapeutic potential in impeding tumour growth and metastatic ability of cancer stem cells.

(±)-Perforison A, A Pair of New Chromone Enantiomers from Harrisonia perforata.

(+)-Perforison A and (-)-perforison A, a new pair of chromone enantiomers, along with four known compounds, were isolated from the leaves and stems of Harrisonia perforata. Their structures and absolute configurations were determined on the basis of extensive analysis of spectroscopic data and electronic circular dichroism (ECD) calculations. The cytotoxic activities in vitro of these compounds were evaluated, but none showed significant activity.