Activity of Semi-Synthetic Mulinanes against MDR, Pre-XDR, and XDR Strains of Mycobacterium tuberculosis.

Tuberculosis causes more than 1.2 million deaths each year. Worldwide, it is the first cause of death by a single infectious agent. The emergence of drug-resistant strains has limited pharmacological treatment of the disease and today, new drugs are urgently needed. Semi-synthetic mulinanes have previously shown important activity against multidrug-resistant (MDR) Mycobacterium tuberculosis. In this investigation, a new set of semi-synthetic mulinanes were synthetized, characterized, and evaluated for their in vitro activity against three drug-resistant clinical isolates of M. tuberculosis: MDR, pre-extensively Drug-Resistant (pre-XDR), and extensively Drug-Resistant (XDR), and against the drug-susceptible laboratory reference strain H37Rv. Derivative 1a showed the best anti-TB activity (minimum inhibitory concentration [MIC] = 5.4 µM) against the susceptible strain and was twice as potent (MIC = 2.7 µM) on the MDR, pre-XDR, and XDR strains and also possessed a bactericidal effect. Derivative 1a was also tested for its anti-TB activity in mice infected with the MDR strain. In this case, 1a produced a significant reduction of pulmonary bacilli loads, six times lower than the control, when tested at 0.2536 mg/Kg. In addition, 1a demonstrated an adjuvant effect by shortening second-line chemotherapy. Finally, the selectivity index of >15.64 shown by 1a when tested on Vero cells makes this derivative an important candidate for future studies in the development of novel antitubercular agents.

Further mulinane and azorellane diterpenoids isolated from Mulinum crassifolium and Azorella compacta.

The new mulinane diterpenoids 1 and 2 were isolated from the EtOAc extract of Mulinum crassifolium, while the rearranged mulinane 5, which was isolated for the first time from a natural source, was isolated from Azorella compacta. Compounds 1-2 were prepared by semi-synthesis thorough acetylation of the diterpene 17-acetoxymulinic acid (3). A mechanism of reaction was proposed, while the structures of the new compounds were elucidated on the basis of comprehensive spectroscopic analysis and computational methods.

A new azorellane diterpenoid from Azorella madreporica.

A new azorellane diterpenoid has been isolated and identified from the aerial parts of Azorella madreporica Clos. The structure of 1 was established by one- and two-dimensional NMR techniques.

An orthorhombic polymorph of mulinic acid.

THE TITLE COMPOUND [SYSTEMATIC NAME: (3S,3aS,10bR)-3-isopropyl-5a,8-dimethyl-2,3,4,5,5a,6,7,10,10a,10b-deca-hydro-endo-epidioxy-cyclo-hepta-[e]indene-3a(1H)-carboxylic acid], C(20)H(30)O(4), is a polymorphic form of a previously reported structure [Loyola et al. (1990 ▶). Tetra-hedron, 46, 5413-5420]. The newly found ortho-rhom-bic polymorph crystallizes in P2(1)2(1)2(1) with two mol-ecules in the asymmetric unit. The mol-ecules are linked into discrete D(2) chains by simple O-H⋯O inter-actions. There are only slight variations in the mol-ecular geometry and supra-molecular organization in the crystal structures of the two polymorphs. The densities are 1.145 (monoclinic, P2(1)) and 1.155 Mg m(-3) (ortho-rhom-bic, P2(1)2(1)2(1)).

(1R,3aR,5aS,6S,8aR,8bR,9aS)-1-Hydr-oxy-6-isopropyl-1,3a,5a-trimethyl-perhydro-cyclo-penta-[a]cyclo-propa[i]naphthalen-4-one.

The title compound (also know as azorellanone), C(20)H(32)O(2), is built up from three fused carbocycles, one five-membered ring and two six-membered rings. The five membered-ring has an envelope conformation, whereas the six-membered rings have a distorted half-chair and a twist-boat conformation. In the crystal, mol-ecules are linked by O-H⋯O inter-actions into zigzag chains with graph-set notation C(8) along [010]. The absolute configuration was assigned on the basis of earlier chemical studies.

Antituberculosis activity of alkylated mulinane diterpenoids.

Natural azorellane and mulinane diterpenoids show antituberculosis activity, which is increased by methylation of their free carboxyl group. We have systematically investigated the effect of alkylation in this class of diterpenoids and found that the profile of bioactivity is relatively unaffected by the introduction of short alkyl groups, both linear and branched. In this investigation, three semisynthetic diterpenoids, 13 hydroxy-mulin-11-en-20-oic acid n-propyl ester (3) and the n-propyl (19) and n-butyl (20) esters of isomulinic acid, showed the strongest antituberculosis activity (MIC=6.25 microg/mL) against a drug-resistant strain of Mycobacterium tuberculosis.

Antituberculosis activity of natural and semisynthetic azorellane and mulinane diterpenoids.

The antituberculosis activity of 14 natural azorellane and mulinane diterpenoids isolated from Azorella compacta, Azorella madreporica, Mulinum crassifolium, and Laretia acaulis, together with eight semisynthetic derivatives, was evaluated against two Mycobacterium tuberculosis strains. The natural azorellanes azorellanol (3) and 17-acetoxy-13-alpha-hydroxyazorellane (6), and the semisynthetic mulinanes 13-hydroxy-mulin-11-en-20-oic-acid methyl ester (13) and mulinenic acid methyl ester (23), showed the strongest activity, with MIC values of 12.5 microg/mL against both strains. The methylated derivatives 13-hydroxy-mulin-11-en-20-oic-acid methyl ester (13), mulin-11,13-dien-20-oic acid methyl ester (15) and mulinenic acid methyl ester (23) proved to be more active than the parent compounds.

Aromaticine, a sesquiterpene lactone from Amblyopappus pusillus.

AROMATICINE (SYSTEMATIC NAME: 4a,8-dimethyl-3-methyl-ene-3,3a,4,4a,7a,8,9,9a-octa-hydro-azuleno[6,5-b]furan-2,5-dione), C(15)H(18)O(3), is a natural lactone isolated from Amblyopappus pusillus. The mol-ecular structure and conformation agree with the results of Romo, Joseph-Nathan & Díaz [(1964 ▶). Tetra-hedron, 20, 79-85]. The fused-ring system contains a seven-membered ring in a twist-boat conformation and two five-membered rings trans fused in envelope conformations.

Methyl 5a-acetoxy-methyl-3-isopropyl-8-methyl-1,2,3,3a,4,5,5a,6,7,10,10a,10b-dodeca-hydro-7,10-endo-epidioxy-cylohepta-[e]indene-3a-carboxyl-ate.

The mol-ecule of the title compound, C(23)H(34)O(6), is built up from three fused carbocycles, one five-membered, one six-membered and one seven-membered. The five-membered ring has an envelope conformation, whereas the six-membered ring has a perfect chair conformation and the seven-membered ring has a boat conformation. Intra-molecular C-H⋯O hydrogen bonds together with van der Waals inter-actions stabilize the mol-ecular conformation.

(3S,3aS,5aS,7S,8S,10aS,10bR)-7,8-Dihydr-oxy-3-isopropyl-5a,8-dimethyl-2,3,4,5,5a,6,7,8,10a,10b-deca-hydro-cyclo-hepta-[e]indene-3a(1H)-carboxylic acid.

The mol-ecule of the title compound, C(20)H(32)O(4), is built up from three fused five-membered, six-membered and seven-membered rings. The five-membered ring has an envelope conformation, whereas the six- and seven-membered rings have chair conformations. The crystal structure is stabilized by strong inter-molecular O-H⋯O hydrogen bonds, forming a three-dimensional network. The absolute configuration was assigned on the basis of earlier chemical studies.

5-Hydr-oxy-7-meth-oxy-4H-chromen-4-one.

The mol-ecular conformation of the title compound, C(10)H(8)O(4), isolated from Laretia acualis, is stabilized by a strong intra-molecular hydrogen bond between the hydroxyl and carbonyl groups. The crystal packing shows π-π stacking inter-actions. The chromene (4H-1-benzopyran-4-one) unit is essentially planar.

Yaretol, a norditerpenoid from Azorella madreporica.

A new norditerpenoid, yaretol (1), was isolated from the whole plant of Azorella madreporica. The structure of 1 was established by one- and two-dimensional NMR techniques and confirmed by X-ray diffraction analysis.

Actividad de diterpenoides de azorella compacta, llareta, sobre amastigotes de trypanosoma cruzi / Activity of dipernoids isolated from azorella compacta, llareta, on trypanosoma cruzi amastigotes

The trypanocidad activity against amastigote forms of SPA-14, Tulahuen and G strains and CL Brener clone of Trypanosoma cruzi of diterpenoids isolated from Azorella compacta. Phil. (Llareta), a plant with ethnomedicinal prestige from prespanish age, was investigated. Amastigocidal activity was shown in azorellanol (2), diterpene isolated by first time, with an inhitory concentration 50 (IC) that varied between 60 M (CL Brener clone) and 84 M (SPA-14 strain), and in mulin -11,13 -dien-20-oico acid (5) with IC between 41 µM (G strain) and 87 mM (CL Brener clone). The cytotoxicity levels of both compounds against Hela and Vero cells and macrophages J144 are lower than nifurtimox and similar to gentian violet