Abraham García

Recent advances in antitubercular natural products

Currently, one third of the worlds population is infected with Mycobacterium tuberculosis and 8.9-9.9 million new and relapse cases of tuberculosis are reported every year. The emergence of new cases, the increased incidence of multi-drug resistant strains of M. tuberculosis, and the adverse effects of first- and second-line antituberculosis drugs have led to renewed research interest in natural products in the hope of discovering new antitubercular leads. Interestingly, hundreds of natural products, possessing novel, uncommon, and known structural architectures, have been reported to exhibit activity towards non-resistant and multi-drug resistant strains of M. tuberculosis. The present review covers literature published during the last five years about those naturally occurring compounds with reported growth inhibitory activity in vitro towards sensitive and resistant M. tuberculosis strains. Compounds with antitubercular properties at minimal inhibitory concentrations (MICs) of less than 50 μg/mL or 60 μM were selected and grouped according to their source of origin (plants, bacteria, fungi, marine organisms, etc) and chemical type (terpenes, steroids, alkaloids, flavonoids, poliketides, peptides, etc). In some cases, the selection covers those structurally relevant natural products with low bioactivity (MICs of ≤128 μg/mL), and also those semisynthetic derivatives with remarkable antitubercular activity (MICs of ≤10 μg/mL). Additionally, this review includes a special section for those natural products that specifically target genes or enzymes of M. tuberculosis.

Chemical Composition of Hexane Extract of Citrus aurantifolia and Anti-Mycobacterium tuberculosis Activity of Some of Its Constituents

The main aim of this study was to isolate and characterize the active compounds from the hexane extract of the fruit peels of Citrus aurantiifolia, which showed activity against one sensitive and three monoresistant (isoniazid, streptomycin or ethambutol) strains of Mycobacterium tuberculosis H37Rv. The active extract was fractionated by column chromatography, yielding the following major compounds: 5-geranyloxypsoralen (1); 5-geranyloxy-7-methoxycoumarin (2); 5,7-dimethoxycoumarin (3); 5-methoxypsoralen (4); and 5,8-dimethoxypsoralen (5). The structures of these compounds were elucidated by 1D and 2D NMR spectroscopy. In addition, GC-MS analysis of the hexane extract allowed the identification of 44 volatile compounds, being 5,7-dimethoxycoumarin (15.79%), 3-methyl-1,2-cyclopentanedione (8.27%), 1-methoxy-ciclohexene (8.0%), corylone (6.93%), palmitic acid (6.89%), 5,8-dimethoxypsoralen (6.08%), α-terpineol (5.97%), and umbelliferone (4.36%), the major constituents. Four isolated coumarins and 16 commercial compounds identified by GC-MS were tested against M. tuberculosis H37Rv and three multidrug-resistant M. tuberculosis strains using the Microplate Alamar Blue Assay. The constituents that showed activity against all strains were 5 (MICs = 25–50 μg/mL), 1 (MICs = 50–100 μg/mL), palmitic acid (MICs = 25–50 μg/mL), linoleic acid (MICs = 50–100 μg/mL), oleic acid (MICs = 100 μg/mL), 4-hexen-3-one (MICs = 50–100 μg/mL), and citral (MICs = 50–100 μg/mL). Compound 5 and palmitic acid were the most active ones. The antimycobacterial activity of the hexane extract of C. aurantifolia could be attributed to these compounds.

Antibacterial and Antimycobacterial Lignans and Flavonoids from Larrea tridentata

Three lignans and four flavonoids were isolated and characterized from Larrea tridentata and compounds were tested against 16 bacterial species/strains. Results showed that: dihydroguaiaretic acid (1) had activity towards methicillin resistant (MR) Staphylococcus aureus (minimum inhibitory concentration (MIC) 50 µg/mL) and multidrug‐resistant (MDR) strains of Mycobacterium tuberculosis (MIC 12.5–50 µg/mL); 4‐epi‐larreatricin (2) was active against Enterobacter cloacae (MIC 12.5 µg/mL), as well as sensitive (MIC 50 µg/mL) and MDR strains of M. tuberculosis (MIC 25 µg/mL). 3′‐Demethoxy‐6‐O‐demethylisoguaiacin (3) displayed activity against sensitive and resistant S. aureus (MIC 25 µg/mL), Enterococcus faecalis (MIC 12.5 µg/mL), Escherichia coli (MIC 50 µg/mL), E. cloacae (MIC 12.5 µg/mL) and MDR strains of M. tuberculosis (MIC 12.5 µg/mL). 5,4′‐Dihydroxy‐3,7,8,3′‐tetramethoxyflavone (4) and 5,4′‐dihydroxy‐3,7,8‐trimethoxyflavone (5) were active against M. tuberculosis MDR strains having MIC values of 25 and 25–50 µg/mL, respectively, while 5,4′‐dihydroxy‐7‐methoxyflavone (6) was active against S. aureus (MIC 50 µg/mL) and E. faecalis (MIC 50 µg/mL). We concluded that lignan 3 is the main compound responsible for the antibacterial activity of L. tridentata. Lignans 1 and 2 as well as flavonoid 6 contribute with some degree of antibacterial activity. On the other hand, compounds 1, 2, 3, 4 and 5 contributed to the antimycobacterial activity found in L. tridentata. Copyright

Neuropeptide Y1 and Y5 Receptor Antagonists as Potential Anti-Obesity Drugs. Current Status.

Among the pharmacological strategies to treat obesity, two subtypes of the neuropeptide Y (NPY) receptor family have drawn the attention of several research groups in the effort to develop efficacious and safe anti-obesity drugs. In the last two decades, different classes of non-peptide compounds exhibiting significant anti-orexigenic responses in NPY knockout and NPY receptor deficient mice have been reported as NPY Y1 and Y5 receptor antagonists. At the beginning of this century, NPY receptor antagonists were considered promising anti-obesity compounds that modulate food intake and body weight in obese patients; however, only a few antagonists are currently being evaluated in clinical trials because there are other neuronal pathways that maintain homeostasis of food intake and body weight in animals, making the design of molecules with more affinity and selectivity for the NPY Y1 and Y5 receptors necessary. The present review is a compendium of the reports that account for the design, synthesis and biological evaluation of non-peptide compounds that selectively bind to NPY Y1 and Y5 receptors. This review presents a historic retrospective of those antagonists that have shown a high affinity and selectivity for these two NPY receptors in preclinical and clinical trials, highlighting key structural features that display more affinity, selectivity, and better pharmacokinetic profiles.

Antitubercular Drugs Development: Recent Advances in Selected Therapeutic Targets and Rational Drug Design

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a remarkably successful pathogen that has latently infected a third of the world population (Zhang et al., 2006). Infection occurs via aerosol, and inhalation of a few droplets containing M. tuberculosis bacilli is enough for lung infection (Hassan et al., 2006). After infection, M. tuberculosis pathogenesis occurs in two stages. The first is an asymptomatic state that can persist for many years in the host, called latent TB. The second stage requires only a weakened immune response to become activated (Zhang, 2004), then the bacteria begins replicating and causing characteristic symptoms such as cough, chest pain, fatigue and unexplained weight loss. If left untreated, the disease eventually culminates in death. The emergence of Human Immunodeficiency Virus (HIV) and the resultant Acquired Immune Deficiency Syndrome (AIDS) pandemic underlined the importance of reactivation of the disease and its potentially catastrophic outcome since over 50% of deaths among HIVinfected patients results from co-infection with M. tuberculosis with the two pathogens inducing each other’s replication, thus accelerating the collapse of the immune system (Cole & Alzari, 2007). While it is impossible to determine the exact number of cases, the latest World Health Organization (WHO) survey estimates that close to 2 million deaths occur every year, that there are approximately 8 million new cases annually, and that every third individual on the planet has been exposed to or infected by M. tuberculosis (Dye, 2006; Cole & Alzari, 2007). Although TB can be treated and even cured with chemotherapy, treatment is exceedingly lengthy and takes 6-9 months (Blumberg, et al., 2003). In addition to significant toxicity, lengthy therapy also causes poor patient compliance, which is a frequent cause for selection of drug resistant and often deadly multidrug resistant TB (MDR-TB) bacteria (Zang et al., 2006). Currently, TB chemotherapy is made up of a cocktail of first-line drugs, isoniazid (INH), Rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB), which are given for six

The solid-state and solution-state reassigned structures of tagitinin A, a 3,10-epoxy-germacrolide from Tithonia diversifolia, and the interconversion of 3,10-epoxy-germacrolide conformational families via a ring-atom flip mechanism

Tagitinina A(2), uma 3,10-epoxi-germacrolida-6,7-trans-lactona conhecida e isolada de Tithonia diversifolia foi estudada atraves de difracao de raios-X de monocristal. Verificou-se que a mesma apresenta a configuracao relativa 1b,4a,6a,7b,8b que difere da orientacao 1a em C(1) proposta originalmente na literatura e que foi determinada pelo metodo de Horeau. Analise do espectro de 1H-RMN de 2 em solucao de d6-acetona mostra que a molecula mantem a conformacao twist-chair-boat (TCB) observada cristalograficamente para o anel de 9 membros. As conformacoes twist-chair-boat/skew-chair-boat do tipo 3 para aneis de 9 membros saturados e insaturados dentro das 3,10-epoxi-germacrolidas podem ser convertidas a conformacao skew-chair-chair (SCC) atraves de mecanismo de inversao de C(9) do anel. Como resultado dessa mudanca conformacional, a orientacao de C(1) e de C(8) da unidade oxicarbonila sao transformados de diequatorial para diaxial. A estereoquimica relatada para lactonas do tipo 3,10-epoxi-germacrolida e resultados de modelagem utilizando-se DFT B3LYP/6-31g(d) indicam que os atomos C(1) tetraedricos estabilizam conformacoes TCB/SCB do tipo 3 enquanto que aqueles com geometria trigonal estabilizam a conformacao SCC.

meso-Dihydroguaiaretic acid derivatives with antibacterial and antimycobacterial activity

Thirty-three meso-dihydroguaiaretic acid (meso-DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculosis strains. Among the tested compounds, four esters (7, 11, 13, and 17), one ether (23), and three amino-ethers (30, 31, and 33) exhibited moderate activity against methicillin-resistant Staphylococcus aureus, whereas 30 and 31 showed better results than levofloxacin against vancomycin-resistant Enterococcus faecium. Additionally, nineteen meso-DGA derivatives displayed moderate to potent activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) values ranging from 3.125 to 50µg/mL. Seven meso-DGA derivatives bearing amino-ethers (26-31 and 33) exhibited the lowest MICs against M. tuberculosis H37Rv and G122 strains, with 31 being as potent as ethambutol (MICs of 3.125 and 6.25µg/mL). The presence of positively charged group precursors possessing steric and hydrophobic features (e.g. N-ethylpiperidine moieties in meso-31) resulted essential to significantly increase the antimycobacterial properties of parent meso-DGA as supported by the R-group pharmacophoric and field-based QSAR analyses. To investigate the safety profile of the antimycobacterial compounds, cytotoxicity on Vero cells was determined. The amino-ether 31 exhibited a selectivity index value of 23, which indicate it was more toxic to M. tuberculosis than to mammalian cells. Therefore, 31 can be considered as a promising antitubercular agent for further studies.

Total synthesis of the natural succinate derivative of 5-(hydroxymethyl)furfural isolated from the Noni fruit (Morinda citrifolia).

Three alternative synthetic routes for the synthesis of naturally occurring n-butyl (5-formylfuran-2-yl)methyl succinate (1) are described. One of them started from furfuryl alcohol (4), and the other two synthetic strategies started from 5-(hydroxymethyl)furfural (6), which could be readily obtained from D-fructose. One of the latter involved a two-step reaction sequence: esterification of 6 with succinic anhydride (5) and esterification of the resultant mono-succinate 2 with n-butyl bromide, to give 1 in 85% overall yield. The second, a one-pot two-step synthesis, consisted of treating 6 with 5 followed by the addition of n-butyl bromide to afford the desired natural product 1 in 85% yield.

Vasodilator Activity of Compounds Isolated from Plants Used in Mexican Traditional Medicine

Arterial hypertension is one of the main risk factors in the development of cardiovascular diseases. Therefore, it is important to look for new drugs to treat hypertension. In this study, we carried out the screening of 19 compounds (triterpenes, diterpenes, sesquiterpenes, lignans, and flavonoids) isolated from 10 plants used in Mexican traditional medicine to determine whether they elicited vascular smooth muscle relaxation and, therefore, could represent novel anti-hypertension drug candidates. The vasorelaxant activity of these compounds was evaluated on the isolated rat aorta assay and the results obtained from this evaluation showed that three compounds induced a significant vasodilatory effect: meso-dihydroguaiaretic acid [half maximal effective concentration (EC50), 49.9 ± 11.2 µM; maximum effect (Emax), 99.8 ± 2.7%]; corosolic acid (EC50, 108.9 ± 6.7 µM; Emax, 96.4 ± 4.2%); and 5,8,4′-trihydroxy-3,7-dimethoxyflavone (EC50, 122.3 ± 7.6 µM; Emax, 99.5 ± 5.4%). Subsequently, involvement of the NO/cyclic guanosine monophosphate (cGMP) and H2S/ATP-sensitive potassium channel (KATP) pathways on the vasodilator activity of these compounds was assessed. The results derived from this analysis showed that the activation of both pathways contributes to the vasorelaxant effect of corosolic acid. On the other hand, the vasodilator effect of meso-dihydroguaiaretic acid and 5,8,4′-trihydroxy-3,7-dimethoxyflavone, partly involves stimulation of the NO/cGMP pathway. However, these compounds also showed an important endothelium-independent vasorelaxant effect, whose mechanism of action remains to be clarified. This study indicates that meso-dihydroguaiaretic acid, corosolic acid, and 5,8,4′-trihydroxy-3,7-dimethoxyflavone could be used as lead compounds for the synthesis of new derivatives with a higher potency to be developed as drugs for the prevention and treatment of cardiovascular diseases.

Synthesis, antimycobacterial evaluation, and QSAR analysis of meso-dihydroguaiaretic acid derivatives

The increasing incidence of new tuberculosis cases and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis have drawn the attention of researchers to the chemical derivatization of promising antimycobacterial natural products. Meso-dihydroguaiaretic acid (meso-DGA) has reported to possess modest activity against sensitive (H37Rv) and resistant M. tuberculosis strains. To improve the antimycobacterial properties of meso-DGA, a series of 19 meso-DGA derivatives bearing carbamates and ethers were synthesized and tested against H37Rv and two MDR strains. Among the carbamates, 2, 3, 5, and 6 exhibited the lowest minimal inhibitory concentration (MIC) values against one MDR strain (MICs of 25 and 12.5 µg/mL), with 6 being the most lipophilic and potent. On the other hand, ethers 10, 12, 14, and 18 showed MIC values in the range of 6.25–50 µg/mL against the three strains, with 14 being the most potent. The larger the chain length in the mono-alkenylated ethers (10, 12, and 14), the lower the MIC value; moreover, a correlation between the chain length of these ethers and the lipophilic character and antimycobacterial activity was observed. The safety profile of the most bioactive derivatives 6 and 14 indicated that 6 (SI > 10) was more toxic to sensitive and MDR strains than to Vero cells, whereas 14 (SI < 3) was more toxic to mammalian cells than to M. tuberculosis strains. Nevertheless, the safety profile of 6 and the potent antimycobacterial activity of 14 make them potential candidates for further studies.