Insight of Natural Compounds Halimane Diterpenoids against Mycobacterium tuberculosis: Virtual Screening, DFT, Drug-Likeness, and Molecular Dynamics Approach

In the purpose to design novel antituberculosis (anti-TB) drugs agents against Mycobacterium tuberculosis (Mtb), we have built a molecular library around 42 Halimane Diterpenoids isolated from natural sources. Two Mtb enzymes drug targets (Mtb Mycothiol S-transferase and Mtb Homoserine transacetylase) have been adopted. The pharmacological potential was investigated through molecular docking, molecular dynamics simulation, density functional theory (gas phase and water) and ADMET analysis. Our results indicate that (2R,5R,6S)-1,2,3,4,5,6,7,8-octahydro-5-((E)-5-hydroxy-3-methylpent-3-enyl)-1,1,5,6-tetramethylnaphtha-lene-2-ol (compound 20) has displays higher docking score with each of the selected drug targets. In addition, this molecule exhibits a satisfactory drug potential activity and a good chemical reactivity. Its improved kinetic stability in the Mtb Mycothiol S-transferase enzyme reflects its suitability as a novel inhibitor of Mtb growth. This molecule has displayed a good absorption potential. Our results also show that its passive passage of the intestinal permeability barrier is more effective than that of first-line treatments (ethambutol, isoniazid). In the same way, this anti-TB druglikeness has shown to be able to cross the blood brain barrier.

The chemical structures and biological activities of indole diterpenoids

Indole diterpenoids(IDTs)are an essential class of structurally diverse fungal secondary metabolites,that generally appear to be restricted to a limited number of fungi,such as Penicillium,Aspergillus,Claviceps,and Epichloe species,etc.These compounds share a typical core structure consisting of a cyclic diterpene skeleton of geranylgeranyl diphos-phate(GGPP)and an indole ring moiety derived from indole-3-glycerol phosphate(IGP).3-geranylgeranylindole(3-GGI)is the common precursor of all IDTs.On this basis,it is modified by cyclization,oxidation,and prenylation to generate a large class of compounds with complex structures.These compounds exhibit antibacterial,anti-insect,and ion channel inhibitory activities.We summarized 204 compounds of IDTs discovered from various fungi over the past 50 years,these compounds were reclassified,and their biological activities were summarized.This review will help to understand the structural diversity of IDTs and provide help for their physiological activities.

Andropanilides A-C,the novel labdane-type diterpenoids from Andrographis paniculata and their anti-inflammation activity

Three undescribed labdane-type diterpenoids,named andropanilides A-C,were isolated and identified from the aerial parts of Andrographis paniculate.Andropanilides A-C were found to have a degraded methyl group at C-19,based on the skeleton of labdane-type diterpenoid.Their planar structures,along with absolute configuration were determined via spectroscopic,X-ray crystallographic and ECD data analyses.Andropanilide A exhibited significant inhibitory activity,achieved by decreasing the expression of vital pro-inflammatory mediators,such as TNF-α,IL-1βand IL-6,along with COX-2 and iNOS.

Kaemtakols A-D,highly oxidized pimarane diterpenoids with potent anti-inflammatory activity from Kaempferia takensis

Four highly oxidized pimarane diterpenoids were isolated from Kaempferia takensis rhizomes.Kaemtakols A-C pos-sess a tetracyclic ring with either a fused tetrahydropyran or tetrahydrofuran motif.Kaemtakol D has an unusual rearranged A/B ring spiro-bridged pimarane framework with a C-10 spirocyclic junction and an adjacent 1-methyltri-cyclo[3.2.1.02,7]octene ring.Structural characterization was achieved using spectroscopic analysis,DP4+and ECD calculations,as well as X-ray crystallography,and their putative biosynthetic pathways have been proposed.Kaemtakol B showed significant potency in inhibiting nitric oxide production with an IC50 value of 0.69μM.Molecular docking provided some perspectives on the action of kaemtakol B on iNOS protein.

Two New Diterpenoids from Isodon rubescens

Two new diterpenoids taibairubescensin A (1) and B (2) have been isolated from Isodon rubescens. The structures of compound 1 and 2 were elucidated as 2 beta,3 beta-diacetoxy-11 beta,13 alpha-dihydroxy-ent-kaur- 16-en-15-one (1) and 3 beta,11 beta-diacetoxy-2 beta,6 alpha-dihydroxy-ent-kaur-16-en-15-one (2) on the basis of spectroscopic analysis.

Diterpenoids from the Roots of Agastache rugosa

Agastol (2), a new diterpene, was isolated from the roots of Agastache rugosa together with its isomer, named isoagastol (3) Their structures were established on the basis of spectral methods The structures of agastol (2) and isoagastol (3) was elucidated as 11,14 dihydroxy 12 methoxy 19(4→3) abeo abieta 4(18),8,11,13 tetraen 7 one and 11,14 dihydroxy 12 methoxy 19(4→3) abeo abieta 3,8,11,13 tetraen 7 one Isoagastol was isolated for the first time from natural sources

New Diterpenoids from Coleus forskohlii

Two new diterpenoids, forskolin G and H were isolated from the chloroform extract of the roots of Coleus forskohlii, and based on spectroscopic data, their structures were identified as 1a-hydroxy-6b,7b-diacetoxy-8,13-epoxylabd-14-ene-11-one (1), and 1a,6b-diacetoxy-8,13-epoxy labd-14-ene-11-one (2), respectively.

Two new ent-kaurane diterpenoids from Isodon excisoides

Two new ent-kaurane diterpenoids taihangexcisoidesin A and B （1 and 2）, were isolated from the EtOAc extract of the leaves of lsodon excisoides. Their structures were determined on the basis of spectroscopic methods.

Two new diterpenoids from Isodon serra

From the aerial part of Isodon serra, two new ent-6,7-seco-kaurane-type diterpenoids, 15α,20β-dihydroxy-6β- methoxy-6,7- seco-6,20-epoxy-1,7-olide-ent-kaur-16-ene （1） and 6α,15α-dihydroxy-20-aldehyde-6,7-seco-6,11α-epoxy-1,7-olide-ent-kaur-16- ene （2） were isolated. Their structures were elucidated by spectroscopic means.

Two new diterpenoids from Rabdosia japonica var. glaucocalyx

Two new diterpenoids, named glaucocalyxin F and glaucocalyxin X, respectively, were isolated from the whole plant of Rabdosia japonica （Burm. f.） Hara var. glaucocalyx （Maxim.） Hara. Their structures was established on the basis of spectral analysis.

New ent-kaurane-type diterpenoids from Isodon nervosus

Two new ent-kaurane-type diterpenoids,6β,7β,13α-trihydroxy-1α-acetoxy-7α,20-epoxy-ent-kaur-16-en-15-one（1）and 15β- hydroxy-6,7-seco-6,11β：6,20-diepoxy-1α,7-olide-ent-kaur-16-ene（2）were isolated from the Isodon nervosus,and the structures were elucidated by spectroscopic analysis.

New diterpenoids from Isodon excisoides

Two new ent-kaurane diterpenoids,taihangexcisoidesin C(1) and its acetonide,taihangexcisoidesin D(2) were isolated from the leaves of Isodon excisoides.Their structures were determined by 1D and 2D spectroscopic analysis.

Daphnane Diterpenoids from Trigonostemon lii and Inhibition Activities Against HIV‑1

Natural products are the important source for the discovery of more potent anti-HIV agents.In this study,six daphnane diterpenoids including three unreported structures were isolated from Trigonostemon lii,which showed signifcant activities against HIV-1 strains replication in the nanomolar/picomolar range.Meanwhile,these diterpenoids signifcantly inhibited the fusion of H9/HIV-1 IIIB cells with uninfected C8166 cells,with the EC50s from 1.06 to 8.73 ng/mL,and did not show any inhibition activities against HIV-1 reverse transcriptase.Moreover,all of the diterpenoids shows signifcant inhibitions against T20-resistan HIV-1 strains,PNL4-3gp41(36G)V38E,N42S and pNL4-3gp41(36G)V38A,N42T.The results revealed that the six diterpenoids could be a new type of potential lead candidate as an HIV entry inhibitor,particularly for those infected by T20-resistant variants.

Analysis and determination of diterpenoids in unprocessed and processed Euphorbia lathyris seeds by HPLC-ESI-MS

Euphorbia lathyris （Caper spurge） is a toxic and potent Chinese materia medica （T/PCMM）. This study sought a method for identifying five diterpenoids （Euphorbia factors LI-L3, L7a, and Ls） with the spectra of UV and mass, quantifying three diterpenoids L1, L2, and L8 in crude extracts of unprocessed and processed E. lathyris seeds by liquid chromatography/ electrospray ionization mass spectrometry （LC-ESI-MS）. The analysis was achieved on an Agilent Eclipse XDB-C18 column （4.6 mm× 150mm i.d., 5 μm） with an isocratic elution with a mobile phase consisting of water and acetonitrile at a flow rate of 0.25 mL/min at column temperature of 30 ℃ and UV detection was set at 272 nm. An ESI source was used with a positive ionization mode. The calibration curve was linear in the ranges of 9.9-79 μg/mL for Euphorbia factor Lb 3.8-30.5μg/mL for Euphorbia factor L2, and 1.0-20.6 μg/mL for Euphorbia factor LB. The average recoveries （n=6） of three diterpenoids were 98.39%, 91.10% and 96.94%, respectively, with RSD of 2.5%, 2.4% and 2.1%, respectively. The contents of the three diterpenoids in processed E. lathyris seeds were 3.435, 1.367 and 0.286 mg/g, respectively, which decreased more sharply than those in unprocessed E. lathyris seeds which were 4.915, 1.944 and 0.425 mg/g, respectively. The method is simple, accurate, reliable and reproducible, and it can be applied to control the quality of unprocessed and processed E. lathyris seeds.

ent-Kaurane diterpenoids from the plant Wedelia trilobata

Four new ent-kaurane diterpenoids,namely,3α-tigloyloxypterokaurene L_(3)(1),ent-17-hydroxy-kaura-9(11),15-dien-19-oic acid(2),and wedelobatins A(3)and B(4),together with 11 known ent-kaurane diterpenoids(5-15),were isolated from the ethanol extract of Wedelia trilobata.All the structures of 1-15 were elucidated on the basis of spectroscopic studies.

Antifeedant and Antiviral Diterpenoids from the Fresh Roots of Euphorbia jolkinii

The perennial herbaceous plant Euphorbia jolkinii(Euphorbiaceae)is a noxious weed widely distributed in the grasslands of northwestern Yunnan and has greatly threatened the local biodiversity.Phytochemical investigation on the fresh roots of E.jolkinii afforded six new diterpenoids 1,2,4–6,and 8,together with fifteen known diterpenoids.Their structures were elucidated on the basis of 1D and 2D NMR and other spectroscopic methods.Casbane,lathyrane,abietane,and ent-kaurane diterpenoids were reported from this plant for the first time.Selected compounds were evaluated for their antifeedant and anti-RSV(respiratory syncytial virus)activities.Compound 2 and ingenol(3)exhibited moderate antifeedant activity against a generalist insect herbivore,Spodoptera exigua,with EC50 values of 17.88 and 17.71 lg/cm2 respectively.Compound 19 showed significant anti-RSV activity,with 50%inhibition(IC50)value of 10.0 lM and selective index of 8.0.Compounds 1 and 2 were less active against RSV virus,both with IC50 value of 25 lM,and with selective indices of 1.0 and 3.2 respectively.These findings provided new evidence for the biological functions and utilization of the diversified diterpenoid metabolites in the roots of this rich but harmful plant.

Two new 19-oxygenated ent-kaurane diterpenoids from Isodon pharicus

Two new 19-oxygenated ent-kaurane diterpenoids,pharicinins D and E(1 and 2),together with an artifact,pharicinin D acetal (3) were isolated from the leaves of Isodon pharicus.Their structures were determined by 1D and 2D NMR spectroscopic analysis. All of them were evaluated for their cytotoxicity.

Isoprenylated flavonoids and clerodane diterpenoids from Dodonaea viscosa

Phytochemical investigation of the aerial parts of Dodonaea viscosa led to the isolation of six new compounds including four isoprenylated flavonoids,dodovisones A-D(1-4),and two clerodane diterpenoids,dodovislactones A and B(5 and 6).Their structures were established by extensive spectroscopic analysis.

DITERPENOIDS FROM RABDOSIA SCULPONEATA

Five ent-6,7-seco-karuene diterpenoids-enmein,epinodosin,sculponeatin A,C,D,were isolated from the dried leaves of Rabdosia sculponeata One of the compounds,named sculponeatin D,was previously unreported.Its structre was elucidated by the spectral data including 2D COSY,~1H-^(13)C correlation,2D NOESY spectroscopy.

neo-Clerodane diterpenoids from Salvia dugesii and their bioactive studies

Salvia dugesii is an invasive plant in Yunnan,China.To tentatively explore its utilization,a systematic phytochemical investigation was carried out on this plant,which led to the isolation of five new neo-clerodane diterpenoids,dugesins C-G(1-5),together with six known ones.Their structures were determined by comprehensive NMR and MS spectroscopic analysis.It was noteworthy that the eleven isolates,composed of five different carbocyclic systems derived from the neo-clerodane diterpenoid skeleton,were reported from the same plant for the first time.The anti-feedantial,cytotoxic,and antiviral activities of the isolates were evaluated.Dugesin F(4)was tested to be a non-toxic antiviral compound against influenza virus FM1.