Updating and profiling the natural product-likeness of Latin American compound libraries.

Compound databases of natural products play a crucial role in drug discovery and development projects and have implications in other areas, such as food chemical research, ecology and metabolomics. Recently, we put together the first version of the Latin American Natural Product database (LANaPDB) as a collective effort of researchers from six countries to ensemble a public and representative library of natural products in a geographical region with a large biodiversity. The present work aims to conduct a comparative and extensive profiling of the natural product-likeness of an updated version of LANaPDB and the individual ten compound databases that form part of LANaPDB. The natural product-likeness profile of the Latin American compound databases is contrasted with the profile of other major natural product databases in the public domain and a set of small-molecule drugs approved for clinical use. As part of the extensive characterization, we employed several chemoinformatics metrics of natural product likeness. The results of this study will capture the attention of the global community engaged in natural product databases, not only in Latin America but across the world.

Navigating the Chemical Space and Chemical Multiverse of a Unified Latin American Natural Product Database: LANaPDB.

The number of databases of natural products (NPs) has increased substantially. Latin America is extraordinarily rich in biodiversity, enabling the identification of novel NPs, which has encouraged both the development of databases and the implementation of those that are being created or are under development. In a collective effort from several Latin American countries, herein we introduce the first version of the Latin American Natural Products Database (LANaPDB), a public compound collection that gathers the chemical information of NPs contained in diverse databases from this geographical region. The current version of LANaPDB unifies the information from six countries and contains 12,959 chemical structures. The structural classification showed that the most abundant compounds are the terpenoids (63.2%), phenylpropanoids (18%) and alkaloids (11.8%). From the analysis of the distribution of properties of pharmaceutical interest, it was observed that many LANaPDB compounds satisfy some drug-like rules of thumb for physicochemical properties. The concept of the chemical multiverse was employed to generate multiple chemical spaces from two different fingerprints and two dimensionality reduction techniques. Comparing LANaPDB with FDA-approved drugs and the major open-access repository of NPs, COCONUT, it was concluded that the chemical space covered by LANaPDB completely overlaps with COCONUT and, in some regions, with FDA-approved drugs. LANaPDB will be updated, adding more compounds from each database, plus the addition of databases from other Latin American countries.

Design and Diversity Analysis of Chemical Libraries in Drug Discovery.

Chemical libraries and compound data sets are among the main inputs to start the drug discovery process at universities, research institutes, and the pharmaceutical industry. The approach used in the design of compound libraries, the chemical information they possess, and the representation of structures, play a fundamental role in the development of studies: chemoinformatics, food informatics, in silico pharmacokinetics, computational toxicology, bioinformatics, and molecular modeling to generate computational hits that will continue the optimization process of drug candidates. The prospects for growth in drug discovery and development processes in chemical, biotechnological, and pharmaceutical companies began a few years ago by integrating computational tools with artificial intelligence methodologies. It is anticipated that it will increase the number of drugs approved by regulatory agencies shortly.

Understanding the Artemia Salina (Brine Shrimp) Test: Pharmacological Significance and Global Impact.

BACKGROUND: The microplate benchtop brine shrimp test (BST) has been widely used for screening and bio-guided isolation of many active compounds, including natural products. Although the interpretation given to the results appears dissimilar, our findings suggest a correlation between positive results with a specific mechanism of action. OBJECTIVE: This study aimed to evaluate drugs belonging to fifteen pharmacological categories having diverse mechanisms of action and carry out a bibliometric analysis of over 700 citations related to microwell BST. METHODS: Test compounds were evaluated in a serial dilution on the microwell BST using healthy nauplii of Artemia salina and after 24 hrs of exposition, the number of alive and dead nauplii was determined, and the LC50 was estimated. A metric study regarding the citations of the BST miniaturized method, sorted by type of documents cited, contributing country, and interpretation of results was conducted on 706 selected citations found in Google Scholar. RESULTS: Out of 206 drugs tested belonging to fifteen pharmacological categories, twenty-six showed LC50 values <100 µM, most of them belonging to the category of antineoplastic drugs; compounds with different therapeutical uses were found to be cytotoxic as well. A bibliometric analysis showed 706 documents citing the miniaturized BST; 78% of them belonged to academic laboratories from developing countries located on all continents, 63% interpreted their results as cytotoxic activity and 35% indicated general toxicity assessment. CONCLUSION: BST is a simple, affordable, benchtop assay, capable of detecting cytotoxic drugs with specific mechanisms of action, such as protein synthesis inhibition, antimitotic, DNA binding, topoisomerase I inhibitors, and caspases cascade interfering drugs. The microwell BST is a technique that is used worldwide for the bio-guided isolation of cytotoxic compounds from different sources.

Anti-Trypanosomal Bufadienolides from the Oocytes of the Toad Rhinella alata (Anura, Bufonidae).

Amphibians are widely known as a prolific source of bioactive metabolites. In this work, we isolated and characterized compounds with antiparasitic activity from the oocytes of the toad Rhinella alata collected in Panama. Bio-guided isolation and structural elucidation were carried out using chromatographic and spectroscopic techniques, respectively. The organic extract was subjected to solid phase extraction followed by HPLC purification of the fraction with in vitro activity against Trypanosoma cruzi trypomastigotes. Seven steroids (1-7) of the bufadienolide family were isolated, and their structures were determined using NMR and MS analyses; of these 19-formyl-dyscinobufotalin, (3) is reported as a new natural product. Compounds 1 and 3-7 resulted in a good anti-trypanosomal activity profile. Among these, 16ß-hydroxyl-hellebrigenin (1) and bufalin (7) showed significant selectivity values of >5 and 2.69, respectively, while the positive control benznidazole showed a selectivity of 18.81. Furthermore, molecular docking analysis showed compounds 1, 3 and 7 interact through H-bonds with the amino acid residues GLN-19, ASP-158, HIS-159 and TRP-177 from cruzipain at the catalytic site. Given the lack of therapeutic options to treat American trypanosomiasis, this work can serve as the basis for further studies that aim for the development of bufadienolides or their derivatives as drugs against Chagas disease.

Latin American databases of natural products: biodiversity and drug discovery against SARS-CoV-2.

In this study, we evaluated 3444 Latin American natural products using cheminformatic tools. We also characterized 196 compounds for the first time from the flora of El Salvador that were compared with the databases of secondary metabolites from Brazil, Mexico, and Panama, and 42 969 compounds (natural, semi-synthetic, synthetic) from different regions of the world. The overall analysis was performed using drug-likeness properties, molecular fingerprints of different designs, two parameters similarity, molecular scaffolds, and molecular complexity metrics. It was found that, in general, Salvadoran natural products have a large diversity based on fingerprints. Simultaneously, those belonging to Mexico and Panama present the greatest diversity of scaffolds compared to the other databases. This study provided evidence of the high structural complexity that Latin America's natural products have as a benchmark. The COVID-19 pandemic has had a negative effect on a global level. Thus, in the search for substances that may influence the coronavirus life cycle, the secondary metabolites from El Salvador and Panama were evaluated by docking against the endoribonuclease NSP-15, an enzyme involved in the SARS CoV-2 viral replication. We propose in this study three natural products as potential inhibitors of NSP-15.

Cheminformatic characterization of natural products from Panama.

In this work, we discuss the characterization and diversity analysis of 354 natural products (NPs) from Panama, systematically analyzed for the first time. The in-house database was compared to NPs from Brazil, compounds from Traditional Chinese Medicine, natural and semisynthetic collections used in high-throughput screening, and compounds from ChEMBL. An analysis of the "global diversity" was conducted using molecular properties of pharmaceutical interest, three molecular fingerprints of different design, molecular scaffolds, and molecular complexity. The global diversity was visualized using consensus diversity plots that revealed that the secondary metabolites in the Panamanian flora have a large scaffold diversity as compared to other composite databases and also have several unique scaffolds. The large scaffold diversity is in agreement with the broad range of biological activities that this collection of NPs from Panama has shown. This study also provided further quantitative evidence of the large structural complexity of NPs. The results obtained in this study support that NPs from Panama are promising candidates to identify selective molecules and are suitable sources of compounds for virtual screening campaigns.

Neoflavonoids as Inhibitors of HIV-1 Replication by Targeting the Tat and NF-κB Pathways.

Twenty-eight neoflavonoids have been prepared and evaluated in vitro against HIV-1. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase reporter gene. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Seven 4-phenylchromen-2-one derivatives showed HIV transcriptional inhibitory activity but only the phenylchrome-2-one 10 inhibited NF-κB and displayed anti-Tat activity simultaneously. Compounds 10, 14, and 25, inhibited HIV replication in both targets at concentrations <25 µM. The assays of these synthetic 4-phenylchromen-2-ones may aid in the investigation of some aspects of the anti-HIV activity of such compounds and could serve as a scaffold for designing better anti-HIV compounds, which may lead to a potential anti-HIV therapeutic drug.

Two new alkylresorcinols from Homalomena wendlandii and their cytotoxic activity.

In the course of our search for antineoplasic agents from Panamanian Flora, two new alkylresorcinols: 1-(2,6-dihydroxyphenyl)octan-l-one (1) and (+)-1-(3-(1-(2,6-dihydroxyphenyl)butyl)-2,6-dihydroxyphenyl)octan-l-one (2), together with three known compounds, (1R, 2R)-l-(benzo[d][1,3]dioxol-5-yl)propane-1,2,3-triol (3), (+)-aptosimon (4) and (-)-sesamin (5), were identified from the leaves of Homalomena wendlandii Schott (Araceae). Their structures were established by 1D and 2D NMR and IR spectroscopic, and MS methods. Compound 2 exhibited IC50 values of 3.3, 5.8 and 4.0 microg/mL against MCF-7, SF-268 and H-460 cancer human cell lines, respectively.

3-Phenylcoumarins as inhibitors of HIV-1 replication.

We have synthesized fourteen 3-phenylcoumarin derivatives and evaluated their anti-HIV activity. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase gene as reporter. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Six compounds displayed NF-κB inhibition, four resulted Tat antagonists and three of them showed both activities. Three compounds inhibited HIV replication with IC50 values < 25 µM. The antiviral effect of the 4-hydroxycoumarin derivative 19 correlates with its specific inhibition of Tat functions, while compound 8, 3-(2-chlorophenyl)coumarin, seems to act through a mechanism unrelated to the molecular targets considered in this research.

Vasoactive effects of different fractions from two Panamanians plants used in Amerindian traditional medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Cecropia obtusifolia (Cecropiaceae) and Psychotria poeppigiana (Synonym: Cephaelis elata, Rubiaceae) are two Latin American plants broadly used in traditional Amerindian medicine. The former, together with many other species of the genus Cecropia, share the folk reputation of curing heart failure, cough, asthma and bronchitis. The latter is used in Panama by Kuna and Ngäbe Buglé (Guaymies) native Indians for the treatment of dyspnea. AIM OF THE STUDY: Based on screening of selected medicinal Panamanian plants by radioligand-binding techniques by Caballero-George et al. (2001), the present study was carried out in order to investigate the vasoactive effects of different fractions from both P. poeppigiana and C. obtusifolia on rat thoracic aorta and identify active fractions and their chemical constituents. MATERIALS AND METHODS: Both acid and neutral methanol fractions (P-AMeOH and P-NMeOH) and acid and neutral dichlorometane fractions (P-ADCM and P-NDCM) were obtained from P. poeppigiana crude methanolic and dichlorometane extracts, respectively. Identical fractionation was carried out for C. obtusifolia (C-AMeOH, C-NMeOH, C-ADCM and C-NDCM. Vasorelaxant effect of all fractions, and their inhibition of contractile responses to angiotensin II were evaluated in isolated aortic rings. RESULTS: P-AMeOH, P-NMeOH and P-ADCM fractions induced a concentration-dependent relaxation (43.9+/-1.8%, 35.3+/-4.7% and 52.9+/-3.5%, respectively) in the endothelium-intact aorta precontracted by phenylephrine (PE, 10(-6)M). The relaxation produced by C-AMeOH and C-NMeOH (57.3+/-2.5% and 53.3+/-3.3%, respectively) was greater than the effect produced by C-ADCM and C-NDCM (42.2+/-3.4% and 21.8+/-0.8%, respectively). Only the incubation of the aortic rings with P-AMeOH reduced the maximum contraction induced by angiotensin II at 20.08+/-0.55%. CONCLUSIONS: The direct vasorelaxation effect observed could explain in part the ethnomedical use of these plants in Amerindian traditional medicine. The most active fractions contain phenolic and aromatic acid compounds. Furthermore, P-AMeOH, the only fraction that showed both vasorelaxant effect and inhibition of contractile responses to angiotensin II, is the most rich in aromatic acids compounds and the only one that contains scopoletin.

Composition and biological activity of essential oils from Protium confusum.

The composition and biological activity of the essential oils from leaves, fruits, stems and bark of Protium confusum are reported for the first time. Forty-six to sixty-three constituents were identified ranging from 73.8% to 98.5% of the samples. Limonene (60.2%) was the main component in the fruit oil, whereas spathulenol (19.3%), beta-caryophyllene oxide (14.1%) and beta-caryophyllene (8.0%) reached the highest percentages in the oil from leaves. The volatile oils from bark and stems showed the same major constituents: p-cymen-8-ol (14.4% and 6.1%, respectively), spathulenol (9.5% and 9.0% respectively), and hexadecanoic acid (8.4% and 7.8%, respectively). The composition of the essential oils differed significantly from those of previously investigated Protium species. Three out of the four samples exhibited antibacterial activity against Staphylococcus aureus and Mycobacterium smegmatis, the one from leaves being the most active, with MIC values of 62.5 microg/mL in both cases. No activity against Candida albicans was detected. The bark oil showed the highest larvicidal activity against Aedes aegypti (LC100 = 125 microg/mL).

Vasorelaxant properties of acid and neutral fractions of Dimerocostus strobilaceus Kuntze used by Kuna Indians of Panama.

ETHNOPHARMACOLOGICAL RELEVANCE: Dimerocostus strobilaceus is used by the Kuna Indians of Panama for the treatment of hypertension and other cardiovascular diseases. AIM OF THE STUDY: We investigated the vascular effects of acid and neutral fractions obtained from methanol and dichloromethane extracts of Dimerocostus strobilaceus. MATERIALS AND METHODS: The acid and neutral methanol fractions (A-MeOH and N-MeOH) or acid and neutral dichlorometanic fractions (A-DCM and N-DCM) were tested using isolated rat aortic rings with or without endothelium pre-contracted by phenylephrine. We examined the ability of these different fractions at different concentrations to modify vascular responses induced by angiotensin II using endothelium-denuded aortic rings from Spontaneously Hypertensive Rats (SHR). RESULTS: In aortic rings with intact endothelium A-MeOH, N-MeOH and A-DCM fractions produced a concentration-dependent vasorelaxation (62.4 +/- 5.2, 64.5 +/- 5.0 and 63.7 +/- 5.0%, respectively), whereas the N-DCM fraction did not produce any vasorelaxant effect. Maximal relaxation evocated by vasoactive fractions was substantially inhibited on aortic rings without endothelium.Our study demonstrates that A-MeOH, N-MeOH, A-DCM and N-DCM significantly reduce contractile responses induced by angiotensin-II on aortic rings. CONCLUSIONS: Our findings may contribute to a better understanding of the potential link between vascular properties observed with Dimerocostus strobilaceus and their ethnobotanical use.

A new cytotoxic friedelane acid--pluricostatic acid--and other compounds from the leaves of Marila pluricostata.

Bioassay-guided fractionation of the dichloromethane extract of the leaves of Marila pluricostata led to the isolation of 2alpha,3beta-dihydroxy-D:A-friedoolean-28-oic acid (pluricostatic acid), a new friedelane triterpenoid, (1), ten known triterpenoids and three sterols. Their chemical structures were elucidated through spectroscopic analysis. The less polar fractions, on GC/MS analysis and comparison with a MS library, resulted in the identification of twenty four sesquiterpenoids. The new triterpenoid acid 1 showed cytotoxicity against the MCF-7, H-460, and SF-268 human cancer cell lines with GI(50) values from 1.2 to 3.3 microg/mL.

Cytotoxic and antimicrobial benzophenones from the leaves of Tovomita longifolia.

Bioassay-guided fractionation of the chloroform and ethanol extracts of Tovomita longifolia leaves using cytotoxic and antimicrobial assays resulted in the isolation of four new benzophenones, (E)-3-(2-hydroxy-7-methyl-3-methyleneoct-6-enyl)-2,4,6-trihydroxybenzophenone (1), (E)-3-(6-hydroxy-3,7-dimethylocta-2,7-dienyl)-2,4,6-trihydroxybenzophenone (2), 8-benzoyl-2-(4-methylpenten-3-yl)chromane-3,5,7-triol (3), and 5-benzoyl-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-6,8-diol (4), and two known benzophenones, 4-geranyloxy-2,6-dihydroxybenzophenone (5) and 3-geranyl-2,4,6-trihydroxybenzophenone (6). The structures of 1-4 were established by spectroscopic means and by molecular modeling calculations. Compounds 1 and 3-5 demonstrated cytotoxic activities against breast (MCF-7), central nervous system (SF-268), and lung (H-460) human cancer cell lines, while compounds 3-6 showed antimicrobial activity against Klebsiella pneumoniae, Mycobacterium smegmatis, Pseudomonas aeruginosa, Salmonella gallinarum, and Staphylococcus aureus.

4-Phenylcoumarins as HIV transcription inhibitors.

We have evaluated the anti-HIV activity of eleven natural 4-phenylcoumarins isolated from Marila pluricostata and three of their derivatives. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase gene as reporter. Inhibitions of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Most of the coumarins tested displayed NF-kappaB inhibition. Two coumarins were also Tat antagonists and the presence of both activities correlated with a stronger inhibition of HIV replication. Our results show that antiviral effect of 4-phenylcoumarins can be related to the inhibition of NF-kappaB and Tat, and suggest that these types of compounds can be useful in the treatment of HIV infection as viral transcription inhibitors.

Cytotoxic 4-phenylcoumarins from the leaves of Marila pluricostata.

Bioassay-guided fractionation of the CH(2)Cl(2) extract of the leaves of Marila pluricostata led to the isolation of 17 naturally occurring 4-phenylcoumarins, three of them, 5-hydroxy-8,8-dimethyl-4-phenyl-9,10-dihydro-8H-pyrano-[2,3-f]chromen-2-one (1), 5-hydroxy-8,8-dimethyl-4-phenyl-6-propionyl-9,10-dihydro-8H-pyrano-[2,3-f]chromen-2-one (2), and 5,7-dihydroxy-8-(3-methylbut-2-enyl)-4-phenylchromen-2-one (3), are new natural compounds; the remaining (4-17) are known mammea-type coumarins. Their structures were established by spectroscopic means. All compounds were tested in cytotoxicity assays against the MCF-7, H-460, and SF-268 human cancer cell lines.

A New Larvicidal Lignan from Piper fimbriulatum.

A new lignan, 3,4,5'-trimethoxy-3',4'-methylenedioxy-7,9':7',9 diepoxylignan (1) (6-[4-(3,4-dimethoxy-phenyl)-tetrahydro-furo[3,4-c.]furan-1-yl]-4-methoxy-benzo[ ] dioxole) together with two known lignans, 7'-epi.-sesartemin (2) and diayangambin (3), and a known flavonoid, 5-hydroxy-7,4'-dimethoxyflavone (4), were isolated from the leaves of Piper fimbriulatum. C. DC. Their structures were assigned by a combination of one- and two-dimensional NMR techniques. 7'-epi.-Sesartemin (2) showed the highest larvicidal activity against Aedes aegypti. (LC100 17.6 µg/ml) and weak antiplasmodial (IC50 7.0 µg/ml) and antitrypanosomal (IC50 39.0 µg/ml) activities. None of the compounds was active against Leishmania mexicana..

Diayangambin exerts immunosuppressive and anti-inflammatory effects in vitro and in vivo.

In this study, the furofuran lignan (+)-diayangambin [tetrahydro-1,4-bis(3,4,5-trimethoxyphenyl)-(1 R)-1alpha,3abeta,4alpha,6abeta-1 H,3 H-furo [3,4- c]furan] was evaluated in vitro and in vivo for its immunomodulatory and anti-inflammatory efficacy. Human mononuclear cell proliferation was inhibited by diayangambin with an IC 50 value of 1.5 (0.5 - 2.8) microM. In addition, the compound reduced for 40.8 % prostaglandin E 2 generation in stimulated RAW 264.7 macrophage cell line at 10 microM. In vivo, a clear reduction of ear swelling was observed when diayangambin (40 mg/kg) was administered orally to 2,4-dinitrofluorobenzene-treated mice. The inhibition of swelling was associated with a reduction of leukocyte infiltration determined as myeloperoxidase activity. In the carrageenan mouse paw edema model, diayangambin significantly suppressed inflamed paw volume and prostaglandin E 2 levels. Our findings indicate the potential interest of diayangambin in the treatment of immune and inflammatory responses.