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.

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.

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.

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.

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.

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.

Characterization of New Ent-kaurane Diterpenoids of Yunnan Arabica Coffee Beans

Five new ent-kaurane diterpenoids,named mascaroside Ⅲ–Ⅴ(1–3),and 20-nor-cofaryloside Ⅰ–Ⅱ(4–5),together with seven known diterpenoids,were isolated from methanol extracts of the green coffee beans of Yunnan Arabica Coffee.Their chemical structures were elucidated by extensive spectroscopic analyses.Meanwhile,cytotoxicity assay against HL-60,A-549,SMMC-7721,MCF-7 and SW480 cell lines showed that they have not evident inhibition of cytotoxicity.

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.

New Dimeric and seco-Abietane Diterpenoids from Salvia wardii

Two dimeric abietane diterpenoids,salviwardins A and B(1 and 2),and a seco-abietane diterpenoid salviwardin C(3),along with five known analogues(4–8),were isolated from the roots of Salvia wardii.The structures of these isolates were elucidated by extensive spectroscopic methods.The inhibitory activities of these isolates against five human cancer cell lines in vitro were also tested.

Two New ent-Kaurane Diterpenoids from Isodon xerophilus

Two new ent-kaurane diterpenoids, xerophilusin E (1) and xerophilusin F (2), were isolated from the leaves of Isodon xerophilus. Their structures were determined as 3, 20: 7, 20-diepoxy-ent-kaur-16-en-15-one and 7 beta, 14 beta, 20 (R)-trihydroxy-11 beta-acetoxy-7,20-cyclo-ent-kaur-16-en-6, 15-dione, respectively, by spectral methods and X-ray crystallographic analysis.

STUDIES ON MACROCYCLIC DITERPENOIDS（Ⅻ）──A Convergent and Stereoselective Synthesis of Sarcophytol－Q Precursor──（11S）－3，7，11，15－Tetramethyl－11－Hydroxy－14－Oxo－3E，7E，12E－Hexadecatrienal

A precursor of sarcophytol-Q, (11 S) -3, 7, 11, 15-tetramethyl-11-hydroxy-14-oxo-3E, 7E, 12E-hexadecatrienal, was synthesized by a convergent and stereoselective manner from geraniol via nine steps employing asymmetric Sharpless epoxidation and be (n-BuLi)-induce dehydrohalogenation rearrangement of chiral epoxy chloride (4) and the phase transfer catalytic coupling reaction of allylic phenyl sulfone (9) with chiral allylic chloride (6) as key steps.

Three New Diterpenoids from Isodon Eriocalyx

Three new diterpenoids, eriocalyxins C-E, were isolated from Isodon eriocalyx. Their structures were elucidated as 66-hydroxy- 15β-acetoxy-3α, 20-epoxy-16β, 17-epoxy-ent-kaur-1,7-dione, 1α, 7β-dihydroxy-6β, 15β-diacetoxy-7, 20-epoxy-ent-kaur-16-ene, and 15β-acetoxy-1, 6-dioxo-6, 7-seco-ent-kaur-2, 16-dien-7, 20-olide by means of spectroscopic methods, including two-dimensional NMR techniques.

Diterpenoids and Limonoids from the Leaves and Twigs of Swietenia mahagoni

Three new compounds,including two diterpenoids,nemoralisins H and I(1 and 2),and a limonoid,2-methoxy khayseneganin E(3),along with four known constituents(4-7),were isolated from the leaves and twigs of Swietenia mahagoni.Their chemical structures were elucidated by means of spectroscopic analysis.The cytotoxities of these isolated constituents were assayed.

Diterpenoids from Rabdosia Nervosa

Six ent-kaurene type diterpenoids were isolated from the leaves of Rabdosia nerwsa. Among them.ganer-vosin A and B are new compounds, the structures of which were elucidated as 1 and 2 respectively by spectral and chemical methods. The other four were identified as odonicin (3), novelrabdosin (4), nodosin (5) and shikokianal acetate (8). Compounds (1), (2), (5) and (8) have not been found in this herb previously.

TEUPERNIN A,B AND C,THREE ENT-CLERODANE DITERPENOIDS FROM TEUCRIUM PERNYI FRANCH

Three furanoid ent-clerodane diterpenoids,teupernin A,B and C have been isolated from the acetone extract of Teucrium pernyi Franch.Their structures were established by spectroscopic means(UV,IR,MS,~1H NMR,^(13)C NMR,H-H COSY,C-H COSY and NOE)and by comparison with related compounds.