Development of New Antimicrobial Oleanonic Acid Polyamine Conjugates

A series of oleanolic acid derivatives holding oxo- or 3-N-polyamino-3-deoxy-substituents at C3 as well as carboxamide function at C17 with different long chain polyamines have been synthesized and evaluated for antimicrobial activities. Almost all series presented good to moderate activity against Gram-positive S. aureus, S. faecalis and B. cereus bacteria with minimum inhibitory concentration (MIC) values from 3.125 to 200 µg/mL. Moreover, compounds possess important antimicrobial activities against Gram-negative E. coli, P. aeruginosa, S. enterica, and EA289 bacteria with MICs ranging from 6.25 to 200 µg/mL. The testing of ability to restore antibiotic activity of doxycycline and erythromycin at a 2 µg/mL concentration in a synergistic assay showed that oleanonic acid conjugate with spermine spacered through propargylamide led to a moderate improvement in terms of antimicrobial activities of the different selected combinations against both P. aeruginosa and E. coli. The study of mechanism of action of the lead conjugate 2i presenting a N-methyl norspermidine moiety showed the effect of disruption of the outer bacterial membrane of P. aeruginosa PA01 cells. Computational ADMET profiling renders this compound as a suitable starting point for pharmacokinetic optimization. These results give confidence to the successful outcome of bioconjugation of polyamines and oleanane-type triterpenoids in the development of antimicrobial agents.

Phytoconstituents of Lantana camara L.: Rekindling Hope in the Cancer Treatment

Background: Lantana camara L. belongs to the family Verbenaceae. It originated in Tropical America in Southern Georgia and to the North of Texas and was introduced in Calcutta, India in the year 1809 as an ornamental hedge. The plant L. Camara is also distributed in Southeast Asia, China, Australia, Brazil, West Indies, Kenya, Mexico, East Africa, Tanzania. Many of its phytoconstituents possess medicinal properties which are used traditionally to treat fever, uterine hemorrhage, and excess menstrual discharge, chronic ulcers, rheumatism, gonorrhea, toothache, gastrointestinal pain, etc, and has been used in Brazil for curing malaria, mange, headaches, colds, and fevers. Objectives: The review elaborates traditional practices, phytochemistry of Lantana camara L. along with the role of Lantana camara in various types of cancers. Method: The data on L. camara was collected through different online databases like Web of Science, PubMed, Science Direct, Springer, and Google Scholar. Results: Major phytoconstituents isolated from the plant shows anticancer activity specially lantadene A-D, icterogenin, oleanolic acid, lantacamaric acid A, B, oleanonic acid, etc. In vitro and in vivo studies demonstrate its potential for various cancers. Certain extracts, isolated compounds, and their semi-synthetic derivatives have depicted a significant cytotoxic and anti-proliferative effect. Conclusion: Clinical studies are not yet established, therefore, making it crucial to direct future researches in that area.

Screening of Botanical Drugs against SARS-CoV-2 Entry

An escalating pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is impacting global health. Specific treatment options for diseases caused by SARS-CoV-2 are largely lacking. Herein, we used a pseudotype virus (pv) bearing the SARS-CoV-2 S glycoprotein to screen a botanical drug library to identify an agent against SARS-CoV-2 entry. All the four hits, including angeloylgomisin O, schisandrin B, procyanidin, and oleanonic acid, were identified for effective inhibition of SARS-CoV-2 S pv entry in the micromolar range. A mechanistic study revealed that these four agents inhibit SARS-CoV-2 S pv entry by blocking S-mediated membrane fusion. Furthermore, angeloylgomisin O, schisandrin B, and oleanonic acid inhibited authentic SARS-CoV-2 with a high selective index (SI). We also showed that all the four hits could also inhibit the entry of pv of Middle East respiratory syndrome coronavirus (MERS-CoV) and newly emerged SARS-CoV-2 variants (D614G, K417N/E484K/N501Y/D614G). In drug combination studies performed in cellular antiviral assays, angeloylgomisin O and schisandrin B displayed synergistic effects in combination with remdesivir. These results indicated that angeloylgomisin O, schisandrin B, procyanidin, and oleanonic acid can inhibit SARS-CoV-2 and that they are potential therapeutic agents for COVID-19.

Bioactive constituents with antibacterial, resistance modulation, anti-biofilm formation and efflux pump inhibition properties from Aidia genipiflora stem bark

Background Antimicrobial resistance is a global health challenge. The involvement of bacterial biofilms and efflux pumps in the development of multidrug resistance (MDR) is well established. Medicinal plants have been proposed as alternatives for combating MDR focusing on their bioactive constituents with resistance modulatory activities. This study was aimed at investigating the stem bark of Aidia genipiflora for bioactive constituents with anti-biofilm, efflux pump inhibition and resistance modulatory activities. Method The crude methanol extract was purified by column chromatography and isolated compounds characterized by mass and nuclear magnetic resonance spectrometry. Antibacterial activity was determined by the High-throughput spot culture growth inhibition and the broth micro-dilution assay. The ethidium bromide accumulation assay was used to determine efflux pump inhibition property. Biofilm inhibition was determined in a microplate crystal violet retention assay. Results Purification of the ethyl acetate fraction led to the isolation of oleanonic acid (1), 4-hydroxy cinnamic acid docosyl ester (2), β-stigmasterol/β-sitosterol (mixture 3a/b) and D-mannitol (4). The minimum inhibitory concentrations (MICs) ranged from 250 to > 500 μg/mL for extracts and fractions and from 15 to 250 μg/mL for compounds. In the presence of sub-inhibitory concentrations of the compounds, the MIC of amoxicillin against E. coli (20 μg/mL) and P. aeruginosa (320 μg/mL) was reduced by 32 and 10 folds respectively. The whole extract demonstrated anti-biofilm formation and efflux pump inhibition in E. coli, S. aureus and P. aeruginosa. The sterol mixture (3a/b) at concentration of 100 μg/mL caused the highest inhibition (73%) of biofilm formation in S. aureus. Oleanonic acid (1) demonstrated remarkable efflux pump inhibition at MIC of 7.8 μg/mL in E. coli better than the standard drugs verapamil and chlorpromazine. Conclusion This study confirms the prospects of A. genipiflora as a source of new antibacterial agents and adjuvants that could interact with some resistance mechanisms in bacteria to enhance the activity of hitherto ineffective antibiotics. “A small portion of the study has been presented in a conference in the form of poster”.

A New Tetrahydrofuran Lignan from Premna serratifolia Wood

Phytochemical investigation of the CHCl3 extract of Premna serratifolia (syn: P. integrifolia) wood collected in Myanmar led to the isolation of a new tetrahydrofuran type lignan, 7,9-dihydroxydolichanthin B (1), together with two known triterpenoids, oleanonic acid (2) and (2a, 3α)-dihydroxyolean-12-en-28-oic acid (3). The structure of the new compound was determined using various spectroscopic techniques, mainly 1D- and 2D-NMR, HRESIMS, IR, and optical rotation, and by comparisons with the reported literatures. Compounds 1-3 had anti-melanin deposition activities against IBMX and α-MSH induced B16-F10 mouse melanoma cell line with IC50 values of 18.4, 17.7 and 11.2 μM, respectively. However, 2 exhibited cytotoxicity at concentrations above 50 μM.

THE HYPOGLYCAEMIC EFFECT OF OLEANONIC ACID ISOLATED FROM PILEA ELIZABETHAE IN A RAT MODEL

Objective: The objective of this study is to isolate and identify the chief hypoglycaemic component of Pilea elizabethaeMethods: The chief hypoglycaemic component of Pilea elizabethaewas isolated and identified. The bio-directed purification of the chief hypoglycaemic agents contained in Pilea elizabethae followed a sequence of steps alternating oral glucose tolerance test (OGTT) bioassay and chromatographic methods. The ethyl acetate crude extract which was most hypoglycaemic in activity was flash chromatographed on silica gel using a gradient hexane-ethyl acetate solvent system of increasing polarity. Elucidation of the chemical structures of R-E2Gii was determined using NMR and FT-IR spectroscopy, melting point determination and comparison with literature. The Pilea elizabethae extracts were tested for hypoglycaemic activity in Sprague-Dawley albino rats using the oral glucose tolerance test (OGTT) method. Isolated hypoglycaemic compounds obtained after bio-directed purification were identified through nuclear magnetic resonance (NMR) spectroscopy and infra-red (IR) spectroscopy.Results: Bio-directed purification of Pilea elizabethae extracts yielded a hypoglycaemic principle that were coded R-E2Gii. By comparison of its NMR chemical shift values and physical properties with literature values, R-E2Gii found to be the triterpenoid oleanonic acid [C30H40O3; M. W=124]. The isolate R-E2Gii demonstrated significant hypoglycaemic activity. When administered intravenously, values were as low as 4.87±0.09 mmol/l thirty minutes post-load compared with 5.63±0.19 mmol/l for the control (p<0.006). An increase in dosage up to 10 mg/kg body weight amplified the post-prandial hypoglycaemic effect of R-E2Gii. Comparison of the hypoglycaemic effect of R-E2Gii with glibenclamide showed that the isolate was only mildly effective in reducing post-prandial hyperglycaemia. Hexane-ethyl acetate extracts from Pilea elizabethae was found to possess anti-hyperglycaemicactivity on OGTT.Conclusion: Bio-directed purification of the hexane-ethyl acetate extracts and using nuclear magnetic resonance (NMR) spectroscopy and infra-red (IR) spectroscopy revealed oleanonic acid, that may be responsible for the anti-hyperglycaemic properties of this extract.

Oleanonic acid from Lippia lupulina (Verbenaceae) shows strong in vitro antileishmanial and antitrypanosomal activity

ABSTRACT Leishmaniasis and Chagas disease affect millions of people in tropical and subtropical regions. Drugs used currently to treat such diseases often present undesirable side effects and low efficiency. The aim of this work was to identify extracts and isolated compounds from the genus Lippia with leishmanicidal and trypanocidal activity. Fifteen extracts from different plant parts of Lippia species with partially known chemical compositions, four partition fractions, six compounds and a mixture of four interconverting flavanones previously isolated from Lippia salviaefolia and Lippia lupulina were assayed in vitro towards epimastigote forms of Trypanosoma cruzi and promastigote forms of Leishmania amazonensis. The root extract of L. lupulina had potent activity against T. cruzi and L. amazonensis (IC50 of 20.0 and 54.5 µg mL-1, respectively). The triterpenoid oleanonic acid showed the strongest activity against these protozoans (IC50 of 18.5 and 29.9 µM, respectively). Our results indicate that Lippia plants and their derivatives deserve further investigation in the search for new antiprotozoal drugs, particularly for the treatment of leishmaniasis and Chagas disease.