First Report on the Synergistic Interaction between Essential Oils against the Pinewood Nematode Bursaphelenchus xylophilus.

Control of the pinewood nematode (PWN), the causal agent of pine wilt disease, can be achieved through the trunk injection of nematicides; however, many pesticides have been linked to environmental and human health concerns. Essential oils (EOs) are suitable alternatives due to their biodegradability and low toxicity to mammals. These complex mixtures of plant volatiles often display multiple biological activities and synergistic interactions between their compounds. The present work profiled the toxicity of eight EOs against the PWN in comparison to their 1:1 mixtures, to screen for successful synergistic interactions. Additionally, the main compounds of the most synergistic mixtures were characterized for their predicted environmental fate and toxicity to mammals in comparison to emamectin benzoate, a commercial nematicide used against PWN. The mixtures of Cymbopogon citratus with Mentha piperita and of Foeniculum vulgare with Satureja montana EOs showed the highest activities, with half-maximal effective concentrations (EC50) of 0.09 and 0.05 µL/mL, respectively. For these, complete PWN mortality was reached after only ca. 15 min or 2 h of direct contact, respectively. Their major compounds had a higher predicted affinity to air and water environmental compartments and are reported to have very low toxicity to mammals, with low acute oral and dermal toxicities. In comparison, emamectin benzoate showed lower nematicidal activity, a higher affinity to the soil and sediments environmental compartments and higher reported oral and dermal toxicity to mammals. Overall, uncovering synergistic activities in combinations of EOs from plants of different families may prove to be a source of biopesticides with optimized toxicity against PWNs.

Evaluation of an Imine-Linked Polymer Organic Framework for Storage and Release of H2S and NO.

Hydrogen sulfide (H2S) and nitric oxide (NO) are especially known as toxic and polluting gases, yet they are also endogenously produced and play key roles in numerous biological processes. These two opposing aspects of the gases highlight the need for new types of materials to be developed in addition to the most common materials such as activated carbons and zeolites. Herein, a new imine-linked polymer organic framework was obtained using the inexpensive and easy-to-access reagents isophthalaldehyde and 2,4,6-triaminopyrimidine in good yield (64%) through the simple and catalyst-free Schiff-base reaction. The polymeric material has microporosity, an ABET surface area of 51 m2/g, and temperature stability up to 300 °C. The obtained 2,4,6-triaminopyrimidine imine-linked polymer organic material has a higher capacity to adsorb NO (1.6 mmol/g) than H2S (0.97 mmol/g). Release studies in aqueous solution showed that H2S has a faster release (3 h) from the material than NO, for which a steady release was observed for at least 5 h. This result is the first evaluation of the possibility of an imine-linked polymer organic framework being used in the therapeutic release of NO or H2S.

Development of a Library of Thiophene-Based Drug-Like Lego Molecules: Evaluation of Their Anion Binding, Transport Properties, and Cytotoxicity.

The anion-binding and transport properties of an extensive library of thiophene-based molecules are reported. Seventeen bis-urea positional isomers, with different binding conformations and lipophilicities, have been synthesized by appending α- or ß-thiophene or α-, ß-, or γ-benzo[b]thiophene moieties to an ortho-phenylenediamine central core, yielding six subsets of positional isomers. Through 1 H NMR, X-ray crystallography, molecular modelling, and anion efflux studies, it is demonstrated that the most active transporters adopt a pre-organized binding conformation capable of promoting the recognition of chloride, using urea and C-H binding groups in a cooperative fashion. Additional large unilamellar vesicle-based assays, carried out under electroneutral and electrogenic conditions, together with N-methyl-d-glucamine chloride assays, have indicated that anion efflux occurs mainly through an H+ /Cl- symport mechanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumor cell lines, while having no effects on a cystic fibrosis cell line.

Antiparasitic Activity of Diterpenoids Against Trypanosoma cruzi.

Twenty-seven diterpenes, including abietanes, labdanes, abeoabietanes, halimanes, and pimaranes, have been evaluated against epimastigote and intracellular amastigote forms of Trypanosoma cruzi and also against LC5 and NCTC cell lines. Royleanones (3, 4, and 5) and a further abietane (12), obtained by purification of Plectranthus spp. extracts, were the most active compounds on epimastigotes, showing IC50 values similar (1.73 µg/mL, 12) or even lower (0.39, 0.99, and 1.20 µg/mL, 3, 4, and 5 respectively) than the positive control nifurtimox (2.3 µg/mL). On intracellular amastigotes, abietanes 3, 4, and 5 showed a significant activity with IC50 values of 0.83, < 0.31, and 0.62 µg/mL, respectively, but were less potent than the positive control nifurtimox (IC50 < 0.16 µg/mL). Compounds 3, 4, and 5 were not cytotoxic to LC5 and NCTC 929 cells at 1 µg/mL.

Chemical composition and antimicrobial activity of essential oil of peruvian dalea strobilacea barneby / Composición química y actividad antimicrobiana del aceite esencialde la planta peruana dalea strobilaceae barneby

The composition of the essential oil obtained by hydrodistillation from Dalea strobilacea Barneby (Fabaceae) aerial parts was examined by GC and GC/MS. beta-Phellandrene (44 percent) together with alpha-pinene (18 percent) were the main essential oil components. Antimicrobial activity of the essential oil was evaluated against eight bacterial strains. A moderate growth inhibition of Klebsiella pneumoniae, Staphylococcus aureus and Enterococcus faecalis was shown by the essential oil.

La composición del aceite esencial de Dalea strobilacea Barneby (Fabaceae) obtenido por hidrodestilación de las partes aereas fue examinada por CG y CG/EM. beta-felandreno (44 por ciento) junto con alfa-pineno (18 por ciento) fueron los principales componentes del aceite esencial. La actividad antimicrobiana del aceite esencial fue evaluada contra ocho cepas bacterianas. El aceite esencial inhibió moderadamente el crecimiento de Klebsiella pneumoniae, Staphylococcus aureus y Enterococcus faecalis.

Bioactivity of Ruta graveolens and Satureja montana Essential Oils on Solanum tuberosum Hairy Roots and Solanum tuberosum Hairy Roots with Meloidogyne chitwoodi Co-cultures.

As a nematotoxics screening biotechnological system, Solanum tuberosum hairy roots (StHR) and S. tuberosum hairy roots with Meloidogyne chitwoodi co-cultures (StHR/CRKN) were evaluated, with and without the addition of the essential oils (EOs) of Satureja montana and Ruta graveolens. EOs nematotoxic and phytotoxic effects were followed weekly by evaluating nematode population density in the co-cultures as well as growth and volatile profiles of both in vitro cultures types. Growth, measured by the dissimilation method and by fresh and dry weight determination, was inhibited after EO addition. Nematode population increased in control cultures, while in EO-added cultures numbers were kept stable. In addition to each of the EOs main components, and in vitro cultures constitutive volatiles, new volatiles were detected by gas chromatography and gas chromatography coupled to mass spectrometry in both culture types. StHR with CRKN co-cultures showed to be suitable for preliminary assessment of nematotoxic EOs.

Larvicidal activity against Aedes aegypti of Foeniculum vulgare essential oils from Portugal and Cape Verde.

Dengue is a potentially fatal mosquito-borne infection with 50 million cases per year and 2.5 billion people vulnerable to the disease. This major public health problem has recurrent epidemics in Latin America and occurred recently in Cape Verde and Madeira Island. The lack of anti-viral treatment or vaccine makes the control of mosquito vectors a high option to prevent virus transmission. Essential oil (EO) constituents can affect insect's behaviour, being potentially effective in pest control. The present study evaluated the potential use of Foenicultm vulgare (fennel) EO in the control of the dengue vector Aedes aegypti. EOs isolated from fennel aerial parts collected in Cape Verde and from a commercial fennel EO of Portugal were analysed by NMR, GC and GC-MS. trans-Anethole (32 and 30%, respectively), limonene (28 and 18%, respectively) and fenchone (10% in both cases) were the main compounds identified in the EOs isolated from fennel from Cape Verde and Portugal, respectively. The larvicidal activity of the EOs and its major constituents were evaluated, using WHO procedures, against third instar larvae ofAe. aegypti for 24 h. Pure compounds, such as limonene isomers, were also assayed. The lethal concentrations LC50, C90 and LC99 were determined by probit analysis using mortality rates of bioassays. A 99% mortality of Ae. aegypti larvae was estimated at 37.1 and 52.4 µL L-1 of fennel EOs from Cape Verde and Portugal, respectively. Bioassays showed that fennel EOs from both countries displayed strong larvicidal effect against Ae. aegypti, the Cape Verde EO being as active as one of its major constituents, (-)-limonene.

Recognition of bio-relevant dicarboxylate anions by an azacalix[2]arene[2]triazine derivative decorated with urea moieties.

A new dichloroazacalix[2]arene[2]triazine receptor (1) with two chiral urea binding moieties is reported. The binding affinity of this macrocycle was evaluated by (1)H NMR titrations in CDCl3 for the dicarboxylate anions oxalate (ox(2-)), malonate (mal(2-)), succinate (suc(2-)), glutarate (glu(2-)), diglycolate (dg(2-)), fumarate (fum(2-)), maleate (male(2-)), and (R,R)- and (S,S)-tartarate (tart(2-)) enantiomers. Among the first five linear anions, the higher association constants were calculated for the larger anions glu(2-) and dg(2-) and for the smallest anion ox(2-), with Kass values following the sequence dg(2-) > glu(2-) > ox(2-) > suc(2-) > mal(2-). Despite the high binding affinity 1 of for both tart(2-) enantiomers, no enantioselectivity was observed. By contrast, Kass for fum(2-) is ca. 8.9 times greater than that for male(2-), showing the selectivity of 1 for the trans isomer. These binding preferences were further elucidated by theoretical methods. Molecular dynamics simulations showed that the linear anions are lodged between both pendant arms and that each anion can assume two distinct binding poses, with one or two carboxylate groups establishing intermittent hydrogen bonds with both urea binding units. On the other hand, the recognition of male(2-) ensues in an alternative scenario, characterised by the interaction between a carboxylate group and a single urea binding unit, mirroring the lower experimental binding affinity relatively to fum(2-). A linear increase of the receptor's Nurea···Nurea and the anions' (-)O2C···CO2(-) distances versus experimental Kass was established for mal(2-), suc(2-), glu(2-) and dg(2-) associations, indicating that the match between these two distances determines the anion binding strength. The affinity for ox(2-) was associated with the most negative values of electrostatic potential positioned near carboxylate groups.

Azacalix[2]arene[2]triazine-based receptors bearing carboxymethyl pendant arms on nitrogen bridges: synthesis and evaluation of their coordination ability towards copper(II).

For functional nitrogen-bridged calix(hetero)aromatic platforms to be further used in the design of more sophisticated receptors, the azacalix[2]arene[2]triazine nitrogen bridges were functionalised with methyl bromoacetate. Three new macrocycles with four N-methyl ester pendant arms were straightforwardly prepared in good yields from the undecorated azacalix[2]arene[2]triazine precursors with chlorine, dimethylamine or dihexylamine substituted triazines. These intermediate macrocycles exhibited different reactivity towards the nucleophilic replacement, which was rationalized from the computed electrostatic potential for these molecules. Subsequently, the N-methyl ester appendages were hydrolyzed with each dialkylamine derivative providing a single macrocycle with four carboxylic groups. In contrast, the hydrolysis of the dichlorinated azacalix[2]arene[2]triazine analogue yielded a mixture of three isomeric macrocycles having two N-methyl esters and two carboxylmethyl pendant arms and the triazine chlorine atoms replaced by hydroxyl groups. The coordination ability of two macrocycles with four carboxylic groups for transition metals was evaluated with copper(ii) by UV-vis titrations.

Evaluation of the structure-activity relationship of rifabutin and analogs: a drug-membrane study.

This work focuses on the influence of rifabutin and two novel analogs, namely, N'-acetyl-rifabutin and N'-butanoyl-rifabutin, on the biophysical properties of lipid membranes. Monolayers and multilamellar vesicles composed of egg L-α-phosphatidylcholine:cholesterol in a molar ratio of 4:1 are chosen to mimic biological membranes. Several accurate biophysical techniques are used to establish a putative relationship between the chemical structure of the antimycobacterial compounds and their activity on the membranes. A combination of in situ experimental techniques, such as Langmuir isotherms, Brewster angle microscopy, polarization-modulated infrared reflection-absorption spectroscopy, and small-angle X-ray scattering, is used to assess the drug-membrane interaction. A relationship between the effect of a drug on the organization of the membranes and their chemical structure is found and may be useful in the development of new drugs with higher efficacy and fewer toxic effects.

Interactions of N'-acetyl-rifabutin and N'-butanoyl-rifabutin with lipid bilayers: a synchrotron X-ray study.

This work focuses on the interaction of N'-acetyl-rifabutin (RFB2) and N'-butanoyl-rifabutin (RFB3) with human and bacterial cell membrane models under physiological conditions. The effect of RFB2 and RFB3 on human cell membrane models was assessed using multilamellar vesicles (MLVs) composed of 1,2-dimyristoyl-rac-glycero-3-phosphocholine (DMPC). In order to mimic the bacterial cell membrane, MLVs of 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DMPG) and a mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) and 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) (8:2 molar ratio) were chosen. Small and wide-angle X-ray scattering (SAXS and WAXS) were used to study the effect of these antimycobacterial compounds on the structure formed in aqueous lipid dispersions. This study contributes to understanding the molecular mechanisms of the drugs delivery through the human and bacterial cells and the effect of these antimycobacterial compounds on the membrane lipids organization, which is related with their antibiotic efficacy and toxic effects.

The influence of rifabutin on human and bacterial membrane models: implications for its mechanism of action.

This work focuses on the interaction of the antibiotic Rifabutin (RFB) with phospholipid membrane models using small- and wide-angle X-ray scattering (SAXS and WAXS) to assess drug-membrane interactions. The effect of different concentrations of RFB on human and bacterial cell membrane models was studied using multilamellar vesicles (MLVs) at the physiological pH (7.4). In this context, MLVs of 1,2-dimyristoyl-rac-glycero-3-phosphocholine (DMPC) were chosen to mimic the human cell membrane. To mimic the bacterial cell membrane, 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DMPG) and a mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) and 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) (8:2 molar ratio) were used. The results support a perturbation of the lipid bilayers caused by RFB, especially in the bacterial membrane model, inducing phase separation that might compromise the integrity of the bacterial membrane. Therefore, the different effects of this antibiotic depending on the concentration, the charge of the phospholipid headgroup, and the membrane organization may be related with the RFB antibiotic activity and the side effects, and should be accounted for during the anti-tuberculosis (anti-TB) drug design.

Effects of a novel antimycobacterial compound on the biophysical properties of a pulmonary surfactant model membrane.

In this work, the interactions of a novel rifabutin's analogue (N'-acetyl-rifabutin, RFB2) with two-dimensional (Langmuir monolayers) and three-dimensional (large unilamellar and multilamellar vesicles) membrane models of the pulmonary surfactant (PS) were evaluated. The main purpose of this study is to obtain detailed information at the molecular level between the interactions of RFB2 with the phospholipids of the PS, under physiological conditions. Therefore, the effects of RFB2 in the monolayer phase behaviour at the air-water interface and in the lipid bilayer of membrane models composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) have been systematically compared. In this context, several biophysical techniques were carried out to establish the interactions of RFB2 with the two-dimensional membrane models of the PS: Langmuir isotherms, Brewster angle microscopy (BAM), and polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS); and with three-dimensional membrane models of the PS: derivate spectrophotometry partition coefficient (Kp), dynamic light scattering (DLS), small and wide angle X-ray scattering (SAXS and WAXS). The results gathered by the different biophysical techniques and the PS membrane model used provide detailed information about the strong interactions of RFB2 with the polar head groups of the PS phospholipids and permit to establish the impact of the RFB2-PS membrane interactions, justifying an often unexplored biophysical approach to the drug's pharmacokinetics and toxicological effect.

Drug-membrane interaction studies applied to N'-acetyl-rifabutin.

This work aims the systematic study of the biophysical interactions of a novel antimycobacterial compound (N'-acetyl-rifabutin, RFB2) with membrane models of different lipid composition and surface charge. Membrane mimetic models were used to evaluate the RFB2's membrane partition, its preferential location across the membrane, and the effect of RFB2 on the biophysical properties of the membrane, which ultimately might be related with the antimycobacterial compound bioavailability and the membrane toxicity. According to the aforementioned, liposomes of dimyristoyl-sn-glycero-phosphocholine (DMPC) and 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) were, respectively, used as mimetic models of human and bacterial cell membranes. The antimycobacterial compound lipophilicity was evaluated by spectroscopic methods, which enabled the determination of the partition coefficient (Kp). To study the RFB2 membrane's location, fluorescence quenching studies and lifetime measurements were executed in liposomes labeled with fluorescent probes. In order to evaluate the changes induced by RFB2 on the membrane biophysical properties, dynamic light scattering (DLS) and steady-state anisotropy were performed. The overall results reveal a strong interaction between RFB2 and the membrane models and allowed the evaluation of its lipophilicity, which is a key molecular descriptor in the characterization of novel potential drugs. Moreover, the higher partition of RFB2 and the more pronounced changes in the biophysical parameters of the negatively charged membrane model suggest that RFB2 has more affinity to the bacterial membrane. For the above-mentioned reasons, this work supports that RFB2 has a potential value as a drug in pharmaceutical formulations used to treat mycobacterial infections.

Essential oil characterization of two Azorean Cryptomeria japonica populations and their biological evaluations.

Essential oils from foliage, bark and heartwood of Cryptomeriajaponica D. Don from Azores Archipelago (Portugal) were analyzed by GC and GC-MS. Two populations, of black and reddish heartwood color, were studied. The main compounds found in the foliage of both populations were alpha-pinene (9.6-29.5%), (+)-phyllocladene (3.5-26.5%), ent-kaur-16-ene (0.2-20.6%), sabinene (0.5-19.9%) and limonene (1.4-11.5%), with a large variation in individual compounds from each population. Heartwood oils were characterized by a high content of cubebol (2.8-39.9%) and epi-cubebol (4.1-26.9%) isomers, which were absent in the foliage. Elemol and eudesmol isomers were found in the foliage and heartwood oils, while (+)-phyllocladene was absent in heartwood. Black and reddish bark oils were composed of the diterpenes dehydroferruginol (1.9-5.1%) and ferruginol (2.6-11.5%), along with the sesquiterpenes delta-cadinene (10.4-15.9%), alpha-muurolene (3.3-5.4%), epi-zonarene (4.0-5.0%), cubenol (9.3-14.0%), tau-muurolol (4.8-10.7%), beta-eudesmol (3.0-9.9%), gamma-eudesmol (1.9-7.0%) and hedycariol (1.4-6.2%). Azorean C. japonica oils exhibited significant chemical differences compared with native plants from Asia. The essential oils showed moderate antimicrobial activity against the pathogenic fungus Cryptococcus neoformans and human pathogenic bacteria (especially against multidrug-resistant Mycobacterium tuberculosis). The antimicrobial activity of the essential oils may be attributed to compounds such as ent-kaur-16-ene, (+)-phyllocladene, ferruginol and elemol, which are present in different proportions within the complex oil mixture. These results suggest a potential use for C. japonica oils obtained from wood industry leftovers.

Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: a biophysical approach to disease.

This work focuses on the interaction of mycolic acids (MAs) and two antimycobacterial compounds (Rifabutin and N'-acetyl-Rifabutin) at the pulmonary membrane level to convey a biophysical perspective of their role in disease. For this purpose, accurate biophysical techniques (Langmuir isotherms, Brewster angle microscopy, and polarization-modulation infrared reflection spectroscopy) and lipid model systems were used to mimic biomembranes: MAs mimic bacterial lipids of the Mycobacterium tuberculosis (MTb) membrane, whereas Curosurf® was used as the human pulmonary surfactant (PS) membrane model. The results obtained show that high quantities of MAs are responsible for significant changes on PS biophysical properties. At the dynamic inspiratory surface tension, high amounts of MAs decrease the order of the lipid monolayer, which appears to be a concentration dependent effect. These results suggest that the amount of MAs might play a critical role in the initial access of the bacteria to their targets. Both molecules also interact with the PS monolayer at the dynamic inspiratory surface. However, in the presence of higher amounts of MAs, both compounds improve the phospholipid packing and, therefore, the order of the lipid surfactant monolayer. In summary, this work discloses the putative protective effects of antimycobacterial compounds against the MAs induced biophysical impairment of PS lipid monolayers. These protective effects are most of the times overlooked, but can constitute an additional therapeutic value in the treatment of pulmonary tuberculosis (Tb) and may provide significant insights for the design of new and more efficient anti-Tb drugs based on their behavior as membrane ordering agents.

Differential interactions of rifabutin with human and bacterial membranes: implication for its therapeutic and toxic effects.

This work focuses on the interaction of rifabutin (RFB), a naphthalenic ansamycin, with membrane models. Since the therapeutic and toxic effects of this class of drugs are strongly influenced by their lipid affinity, we concerned specifically on the ability of this antibiotic to affect the membrane biophysical properties. The extent of the interaction between RFB and membrane phospholipids was quantified by the partition coefficient (K(p)), using membrane model systems that mimic the human (liposomes of 1,2-dimyristoyl-sn-glycero-phosphocholine, DMPC) and the bacterial (liposomes of 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol, DMPG) plasma membranes. To predict the drug location in the membranes, fluorescence quenching and lifetime measurements were carried out using the above-mentioned membrane models labeled with fluorescent probes. Steady-state anisotropy measurements were also performed to evaluate the effect of RFB on the microviscosity of the membranes. Overall, the results support that RFB has higher affinity for the bacterial membrane mediated by electrostatic interactions with the phospholipid head groups.

Molecular interaction of Rifabutin on model lung surfactant monolayers.

Tuberculosis is one of the most relevant problems for global health care. The design of new drugs against tuberculosis is aimed at maximizing impact against the disease, as well as minimizing the toxicological effect on the lung surfactant. In this work, the antituberculosis drug Rifabutin is studied in combination with phospholipid Langmuir monolayers as models of the lung surfactant monolayer. The zwitterionic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and the anionic 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG) were used as model phospholipids. A combination of in situ experimental techniques of Brewster angle microscopy, polarization-modulated infrared reflection-absorption spectroscopy, and UV-vis reflection spectroscopy with computer simulations has been used. The interactions between Rifabutin and the DPPC and DPPG Langmuir monolayers were described as the formation of an inclusion complex. The phospholipid-Rifabutin inclusion complex prevents the penetration of the Rifabutin into the alkyl chain region of the phospholipids, leading to a disruption of the monolayer structure and a possible toxicological effect.

Pharmacophore insights into rpoB gene mutations in Mycobacterium tuberculosis rifampicin resistant isolates.

This paper reports the susceptibility profile to rifabutin (RFB) 1 and six recently synthesized RFB analogs 3-8, of either rifampicin (RFP) susceptible Mycobacterium tuberculosis and resistant clinical isolates from two sources: Mexico and Brazil. Taking into account that about 95% of M. tuberculosis strains resistant to RFP present mutations in the rpoB gene, with some of these mutations being determinant also to RFB resistance, the RFB analogs were screened for activity against a set of known RFP susceptible and resistant strains. N'-Acetyl-RFB 5 and N'-(undec-10″-enoyl)-RFB 8 showed the best results, in particular with mutations in the codon 516, 522 and 531 of the rpoB gene, and were therefore selected for in vivo assessment of their efficacy. Studies conducted with tuberculous Balb/C mice previously infected with Ser531Leu mutated clinical isolate, evidenced both 5 and 8 as promoters of a significant decrease on tubercle bacilli burden in lungs associated with lower tissue damage, thus confirming them as good leads for drug discovery. The SAR of the acylated compounds 5 and 8 envisaging the identification of pharmacophore features, highlights the importance of profiling more clearly the chemistry within the molecular aspects for elucidation of the mode of action of RFB and analogs, in relation to mutations in Multidrug-Resistant (MDR) strains.

Antimycobacterial metabolites from Plectranthus: royleanone derivatives against Mycobacterium tuberculosis strains.

The antimycobacterial activities of eight diterpenes, 1-8, isolated previously from Plectranthus and eleven esters, 9-19, of 7alpha-acetoxy-6beta,12-dihydroxyabieta-8,12-diene-11,14-dione (5) were evaluated against the MTB strains H(37)Rv and MDR. Only diterpenoids with a quinone framework revealed anti-MTB activity. Abietane 5 and its 6,12-dibenzoyl, 12-methoxybenzoyl, 12-chlorobenzoyl, and 12-nitrobenzoyl esters, 9, 11, 12, and 13, respectively, showed potent activities against the MDR strain with MIC values between 3.12 and 0.39 microg/ml. Cytotoxic activities towards 3T3 and Vero cells were also evaluated. Compound 11, with the best selectivity index, may be a suitable lead for further chemical modifications. The complete structural elucidation of the new esters, 9-14, 16, 18, and 19, as well as the NMR data of known derivatives 15 and 17 are reported.