Synthesis of nitrogen-containing monoterpenoids with antibacterial activity

Abstract

Incorporation of the Beckmann rearrangement into the presented research resulted in the formation of nitrogen-containing terpenoid derivatives originating from naturally occurring compounds. Both starting monoterpenes and obtained derivatives were subjected to estimation of their antibacterial potential. In the presented study, Staphylococcus aureus was the most sensitive to examined compounds. The Minimal Inhibitory Concentration (MIC) experiments performed on S. aureus demonstrated that the (?)-menthone oxime (?)-8 and (+)-pulegone oxime (+)-13 had the best antibacterial activity among the tested derivatives and starting compounds. Their MIC₉₀ value was 100?µg/mL. The obtained derivatives were also evaluated for their inhibitory activity against bacterial urease. Among the tested compounds, three active inhibitors were found – oxime 14 and lactams (?)-15 and 16 limited the activity of Sporosarcina pasteurii urease with K_i values of 174.3?µM, 43.0?µM and 4.6?µM, respectively. To our knowledge, derivative 16 is the most active antiureolytic lactam described to date.     

A new depsidone derivative from mangrove sediment derived fungus Lasiodiplodia theobromae

A new depsidone derivative botryorhodine I (1), along with eight known compounds (2-9) were obtained from solid rice cultures of the fungal strain, Lasiodiplodia theobromae M4.2-2 isolated from a mangrove sediment sample. The structures of the isolated compounds were elucidated on the basis of 1?D and 2?D NMR analysis as well as by HRESIMS. All compounds were evaluated for their cytotoxic potential against the mouse lymphoma cell line L5178Y as well as for their antibacterial activities against a panel of Gram-positive and Gram-negative bacterial strains. Compound 3 revealed potent cytotoxic activity with an IC₅₀ of 7.3?µM whereas compound 7 showed selective anti-bacterial activity against different S. aureus and E. faecium bacterial strains with MIC value of 25?µg/ml.     

A new antimicrobial and radical-scavenging glycoside from Paullinia pinnata var. cameroonensis

A new glycoside, pinnatoside A (1), together with two known compounds (2 and 3), were isolated from the stems of Paullinia pinnata. Their structures were elucidated on the basis of extensive spectroscopic analysis and chemical methods. Compound 1 showed significant antibacterial activity with a minimum inhibitory concentration (MIC) value of 1.56 μg/mL against Escherichia coli, and 2 displayed significant antibacterial activity with a MIC value of 1.56 μg/mL against Enterobacter aerogenes and E. coli. Equally, compound 1 exhibited the best radical-scavenging activity (RSa₅₀ = 25.07 ± 0.49 μg/mL).     

Synthesis and evaluation of some new 5-(hetaryl)thiazoles as potential antimicrobial agents

In continuing our efforts to find new effective antimicrobial agents for overcoming the problem of microbial resistance, a new series of functionalized 5-hetarylthiazoles have been designed and synthesized starting from readily accessible 1-(2-allylamino-4-methylthiazol-5-yl)ethanone (3). The structures of newly synthesized compounds were confirmed by elemental analyses, spectral data, and chemical transformations. The synthesized compounds were evaluated in vitro for their antimicrobial activity against some human pathogenic bacterial and fungal strains. The compounds 7, 18, and 24 exhibited higher antibacterial activity with minimum inhibitory concentration (MIC) values ranging from (0.03–0.06?µg/mL) than ampicillin (MIC, 0.12?µg/mL) against Streptococcus pneumoniae. Whereas compounds 4, 22, and 24 revealed higher antifungal potency than amphotericin B against Aspergillus fumigatus. The structure and antimicrobial activity relationship was also discussed.     

Anti-inflammatory activity of saponins from roots of Impatiens parviflora DC.

Abstract

Two triterpene saponins (IPS-1, IPS-2) for the first time were isolated from the roots of Impatiens parviflora DC. (Balsaminaceae). Their anti-inflammatory activity was evaluated by means of two in vitro models: anti-hyaluronidase and anti-denaturation assays. Both saponins were shown to be potent hyaluronidase inhibitors that affect the enzyme in a dose-dependent manner. The anti-hyaluronidase effect of IPS-2 (IC₅₀?=?286.7?µg/mL) was higher than that of the reference drug: escin (IC₅₀?=?303.93?µg/mL). Both saponins protected bovine serum albumin from heat-induced denaturation in a dose-dependent manner. IPS-1 demonstrated higher anti-denaturation effect (IC₅₀?=?86.7?µg/ml) than IPS-2 (IC₅₀?=?109.76?µg/mL) or the standard drug: acetylsalicylic acid (IC₅₀?=?262.22?µg/mL). In conclusion, potent activity of IPS-1, IPS-2 in both in vitro assays shows that saponins from I. parviflora have anti-inflammatory activity. The obtained results allow to suggest that such compounds may be beneficial in inflammatory conditions, especially associated with excessive degradation of hyaluronic acid.     

Facile synthesis of highly functionalized novel pyrazolopyridones using oxoketene dithioacetal and their anti-HIV activity

A series of novel 3-amino-4,5-dihydro-6-methyl-4-oxo-N-aryl-1H-pyrazolo[4,3-c]pyridine-7-carboxamide have been synthesized starting from various oxoketene dithioacetals. The cyclocondensation reaction of 2-(bis(methylthio)methylene)-3-oxo-N-arylbutanamide 2a–w with cyanoacetamide using NaOiPr as base under reflux condition afforded novel highly functionalized pyridone 3a–w derivatives. Further, [3?+?2] cyclocondensation reaction of pyridones with hydrazine in the presence of alcohol was yielded pyrazolopyridones (23 nos) 4a–w with excellent yields. All newly synthesized compounds were evaluated for in vitro anti-HIV activity using MTT method. Most of these compounds have showed moderate to potent activity against HIV-1 (III_B) and HIV-2 (ROD) strains with an IC₅₀ ranging from >18 IC₅₀[µg/ml] to <100 IC₅₀[µg/ml]. Among them, compounds 4j and 4v were identified as the most promising compound for both types of HIV strains. (IC₅₀?=?18?µg/ml). Three compounds 4l, 4m, and 4p have been found potent anti-HIV 1 and 2 activity against MT-4 cells.     

Pestalotiopisorin B,a new isocoumarin derivative from the mangrove endophytic fungus Pestalotiopsis sp. HHL101

Abstract

A new isocoumarin derivative pestalotiopisorin B (1), along with six known compounds, (R)-(-)- mellein methyl ether (2), pestalotiopyrone G (3), (R)-mevalonolactone (4), pestalotiollides A–B (5–6) and pestalotiopsol A(7) were isolated from Pestalotiopsis sp., an endophytic fungus obtained from Chinese mangrove plant Rhizophora stylosa. Their structures were elucidated unambiguously by the comprehensive analysis of extensive spectroscopic data. Compound 1 exhibited modest antibacterial activity against Escherichia coli and Pseudomonas aeruginosa with 12.5?μg/ml, 50?μg/ml, respectively. Compound 4 showed moderate calcineurin inhibitory activity towards p-nitrophenyl phosphate (IC₅₀ =134.29?±?5.377?μM).     

Investigation of antiplasmodial efficacy of lupeol and ursolic acid isolated from Ficus benjamina leaves extract

Abstract

This study emphasizes on the investigation of antiplasmodial activity of triterpenoids isolated from Ficus benjamina leaves. An unsaponified fraction of petroleum ether extract of plant leaves was subjected to silica gel column chromatography which led to the isolation of two known triterpenoids; namely ursolic acid and lupeol. These compounds were evaluated for antiplasmodial activity by schizont maturation inhibition assay using 3D7 Plasmodium strains. Both, ursolic acid and lupeol were found to exhibit significant antiplasmodial effect with an IC₅₀ value of 18?µg/ml and 3.8?µg/ml, respectively. This study further confirms the traditional role of Ficus benjamina plant in the treatment of malaria which may be attributed to ursolic acid and lupeol.     

Chemical constituents of Genista numidica Spach aerial parts and their antimicrobial,antioxidant and antityrosinase activities

A previously undescribed triterpenoid saponin, 3-O-[α-l-rhamnopyranosyl-(1→2)-{β-d-glucopyranosyl-(1→6)-}β-d-galactopyranosyl-(1→2)-β-d-glucuronopyranosyl]-sophoradiol (1), in addition to twenty-nine known constituents (2–30) were isolated from the aerial parts of Genista numidica Spach. Structures elucidation was performed by comprehensive 1D- and 2D-NMR analyses and HRESIMS. The extracts, fractions and isolated compounds were evaluated for their antibacterial, antioxidant and tyrosinase inhibitory activities. The experimental findings indicated that genistin (16), isosalipurpol (27), and koaburaside (29) have moderate to low antibacterial activity against E. faecalis, S. aureus, S. epidermidis and P. aeruginosa bacteria with MICs ranging from 31.2 to 125 μg/mL. Compounds 19 and 27 exhibited a good antiradical activity potential (IC₅₀ 11.8 and 11.1 μg/mL, respectively). Only compounds 23, 27 and 28 exhibited low inhibitory effect against mushroom tyrosinase (IC₅₀ from 90.2 to 225.6 μg/mL).     

Synthesis,antimicrobial activity and QSAR studies of 2,5-disubstituted benzoxazoles

In this study, a new series of 2,5-disubstituted benzoxazoles was synthesized and their structures were elucidated by elemental analysis, MASS, ¹H-NMR, ¹³C-NMR and IR spectral data. Newly and previously synthesized 2,5-disubstituted benzoxazole derivatives were evaluated for antibacterial and antifungal activity against standard strains and their drug-resistant isolates. Microbiological results showed that the compounds presented a large spectrum of activity having MIC values of 250–7.8 µg mL^?1 against the tested microorganisms. Among the newly synthesized derivatives 3–22, compound 11 was the most active against Candida krusei out of all; however, it was one dilution less potent than standard drug fluconazole. In addition, all the new and previous compounds were more active than standard drugs ampicillin trihydrate and rifampicin against Pseudomonas aeruginosa and its gentamicin-resistant isolate. The 2D-QSAR (Quantitative Structure–Activity Relationship) analysis of a set of newly and previously synthesized benzoxazoles tested for growth inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) was also performed by using multivariable regression analysis. The activity contributions for substituent effects of these compounds were determined from the correlation equation for predictions of the lead optimization.     

Antibacterial triterpenoids from the leaves of Ilex hainanensis Merr.

One new triterpenoid (1) and seven known analogues (2–8) were isolated from the leaves of Ilex hainanensis Merr.. Their structures were established by analysis of their MS, 1D and 2D NMR spectroscopic data and comparison with those in the literature. The antibacterial activity of compounds 1–8 were evaluated by determination of minimum inhibitory concentration using twofold microdilution broth method against Streptococcus mutans ATCC 25175 (Gram-positive) and Fusobacterium nucleatum ATCC 10953 (Gram-negative). Compounds 3 and 5 showed significant antibacterial activity against S. mutans in concentration of 9.7 μg/mL, while showed little antibacterial activity against F. nucleatum. On the contrary, the inhibitory activity of compounds 1, 2 and 6 against F. nucleatum were higher than them against S. mutans.     

A novel xanthone dimer derivative with antibacterial activity isolated from the bark of Garcinia mangostana

A novel xanthone dimer derivative, garmoxanthone (1), together with 10 known compounds (2–11), were isolated from bark of Garcinia mangostana. Their structures were established through spectroscopic methods. Garmoxanthone exhibited strong inhibitory activities against MRSA ATCC 43300 and MRSA CGMCC 1.12409 (with MIC values of both 3.9 μg/mL) and moderate activities against tested strains of Vibrio (with MIC values ranging from 15.6 to 31.2 μg/mL). Garmoxanthone is a unique xanthone dimer with linkage of a fused 5/6 ring system and its absolute configuration was elucidated on the basis of experimental and calculated electronic circular dichroism. Garmoxanthone exhibited strong antibacterial activity which partially validated the ethnobotanical use of G. mangostana in the treatment of infections.     

Insecticidal,cytotoxic and anti-phytopathogenic fungal activities of chemical constituents from the aerial parts of Ferula sinkiangensis

Abstract

A new rare monoterpene coumarin (1) and its two known analogues (2–3), together with two sesquiterpenes (6–7) and ferulic acid (8) were isolated from the aerial parts of Ferula sinkiangensis. The structure of new compound was established on the basis of 1D and 2D NMR data and HRESIMS data interpretation. Insecticidal, cytotoxic and anti-phytopathogenic fungal activities of isolated compounds were evaluated against third-instar larvae of Spodoptera exigua and its cell line, and three plant pathogenic fungi respectively. Compounds 1–3 and 6–7 were found to be more effective contact toxicity to S. exigua with the corrected mortality values of 38.89%-58.89% at 10?μg/larva doses for 24?h. Further studies showed that compounds 3 and 6 exhibited cell growth inhibitory activity against S. exigua cell line with the EC₅₀ values of 22.78 and 14.64?µM for 72?h. In addition, compound 6 exhibited potent antifungal activity with MICs?=?16–32?µg/mL.     

One new flavonoid from Oroxylum indicum

One new flavonoid, 5,6,7-trimethoxyflavone-8-O-β-d-glucopyranoside (1), along with six known compounds 2–7, was isolated from Oroxylum indicum. Their structures were determined on the basis of spectral data. The antibacterial activities of compounds 1–4 were studied. Compounds 1 and 3 showed medium antibacterial activity against Staphylococcus aureus with MIC/MBC at 32–128 μg/ml.     

In vitro antimicrobial activity of extracts and compounds isolated from Cladonia uncialis

Heptane (Hep), diethyl ether (Et₂O), acetone (Me₂CO) and methanolic (MeOH) extracts, as well as ( ? )-usnic acid and squamatic acid, were obtained from thallus of Cladonia uncialis (Cladoniaceae). The antimicrobial activities of these extracts, ( ? )-usnic acid and squamatic acid, were tested against reference strains: Staphylococcus aureus, Escherichia coli and Candida albicans. In addition, Me₂CO extract was analysed against 10 strains of Methicillin-resistant S. aureus (MRSA) isolated from patients. All extracts exerted antibacterial activity against the reference strain S. aureus, comparably to chloramphenicol [minimum inhibitory concentration (MIC) = 5.0 μg/mL]. The Me₂CO extract exhibited the strongest activity against S. aureus (MIC = 0.5 μg/mL), higher than ( ? )-usnic acid, whereas squamatic acid proved inactive. The Me₂CO extract showed potent antimicrobial activity against MRSA (MIC 2.5–7.5 μg/mL). Also no activity of C. uncialis extracts against E. coli and C. albicans was observed.     

Terrenolide S,a new antileishmanial butenolide from the endophytic fungus Aspergillus terreus

Terrenolide S, a new butenolide derivative (6), together with six known compounds: (22E,24R)-stigmasta-5,7,22-trien-3-β-ol (1), stigmast-4-ene-3-one (2), stigmasta-4,6,8(14),22-tetraen-3-one (3), terretonin A (4), terretonin (5) and butyrolactone VI (7) have been isolated from the endophytic fungus Aspergillus terreus isolated from the roots of Carthamus lanatus (Asteraceae). Their structures were established by extensive spectroscopic analyses (1D, 2D NMR and HRESIMS), as well as optical rotation measurement and comparison with literature data. Compound 1 displayed a potent activity towards methicillin-resistant Staphylococcus aureus (MRSA) and Cryptococcus neoformans with IC₅₀ values of 2.29 and 10.68 µM, respectively. Moreover, 1, 2 and 6 exhibited antileishmanial activity towards Leishmania donovani with IC₅₀ values of 11.24, 15.32 and 27.27 µM, respectively and IC₉₀ values of 14.68, 40.56 and 167.03 µM, respectively.     

A new antifungal and antiprotozoal bibenzyl derivative from Gavilea lutea

A new bibenzyl derivative (4), together with two glycosylated flavonoids (1 and 2), batatasin III (3) and the phenanthrene isohircinol (5) were isolated from the aerial parts of Gavilea lutea. Their structures were elucidated on the basis of spectroscopic studies including 1D and 2D NMR, UV, IR and HRESIMS. All isolated compounds were evaluated for their antifungal activity towards Candida albicans. The new compound 4 showed inhibitory activity with a MIQ of 50 μg. In addition, compound 4 exhibited a selective activity (IC₅₀ = 2.3 μg/mL) against Leishmania donovani.     

Antibacterial and cytotoxic activities of phenolic constituents from the stem extracts of Spatholobus parviflorus

Abstract

A new 2-arylbenzofuran, spathobenzofuran (1), together with ten known compounds including a 2-arylbenzofuran, three pterocarpans and six isoflavones were isolated from the acetone crude extract of the stems of Spatholobus parviflorus. All compounds were characterised by spectroscopic methods. Compound 4 was active (MIC 8?µg/mL) against Gram-negative Pseudomonas aeruginosa TISTR 781 while compound 2 had modest activity against Gram-positive Staphylococcus aureus TISTR 1466 with a MIC value of 16?µg/mL. All isolated compounds showed no cytotoxicity against Vero and KB cells.     

Two Unusual Phenolic Substances and One New Xanthone from Hypericum sampsonii

Sampsone A ( 1 ), a novel prenylated aromatic lactone, and sampsone B ( 2 ), an unusual dihydrodibenzodioxinone, together with sampsone C ( 3 ), a new xanthone, were isolated from the aerial parts of Hypericum sampsonii. Their structures were determined by spectroscopic methods which were mainly 1D‐ and 2D‐NMR techniques, and the structure of sampsone B ( 2 ) was also confirmed by X‐ray crystallographic analysis. All of these compounds were evaluated for in vitro antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA). Only sampsone A showed moderate antibacterial activities at a minimum inhibitory concentration (MIC) of 32 μg/ml.     

Design,synthesis, antitubercular and antibacterial activities of pyrrolo[3,2-b]pyridine-3-carboxamide linked 2-methoxypyridine derivatives and in silico docking studies

Abstract

A novel series pyrrolo[3,2-b]pyridine-3-carboxamide linked 2-methoxypyridine derivatives have been designed, synthesized and confirmed by FT-IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR, MS, and elemental analysis. The synthesized compounds were screened for their antitubercular activity using microplate alamar blue assay method and antibacterial activity. Among the tested compounds, 4- fluorophenyl (8m), 4- chlorophenyl (8n) and 4-methoxyphenyl (8i) showed potent anti-TB activity (3.12?µg/mL) in comparison with reference drug, Pyrazinamide ((3.12?µg/mL). In addition, all compounds were docked into DprE1 (PDB code: 4KW5) to explore their binding interactions at the active site. The compounds exhibited essential key interactions as that of reported DprE1 inhibitors and hence, the synthesized compounds may be considered as molecular scaffolds for antitubercular activity. Compounds, 4-chlorophenyl (8n) and 4-flurophenyl (8m) showed significant antibacterial activity against Escherichia coli and Staphylococcus aureus strains. In silico prediction of toxicities, druglikeness and drug score profiles of the tested compounds are promising.