Synthesis and Antifungal Activity of 2‐Hydroxy‐4,5‐methylenedioxyaryl Ketones as Analogues of Kakuol

In a study aiming to determine the structural elements essential to the antifungal activity of kakuol, we synthesized a series of 2‐hydroxy‐4,5‐methylenedioxyaryl ketones, and we assayed their in vitro antifungal activity. The most sensitive target organisms to the action of these class of compounds were Phytophthora infestans, Phytium ultimum, Cercospora beticola, Cladosporium cucumerinum, and Rhizoctonia solani. Most of the analogs showed a remarkable in vitro activity, and some of them appeared significantly more effective than the natural product. The biological activity was mainly affected by introducing structural modification on the carbonyl moiety of the natural‐product molecule. In particular, compound 5a , bearing a C?C bond conjugated to the C?O group, was found active with a MIC value of 10 μg ml^?1 against Cladosporium cucumerinum. The results suggest that 2‐hydroxy‐4,5‐methylenedioxyaryl ketones can be considered promising candidates in the development of new antifungal compounds.     

Chemical Composition and Antimicrobial Activity of the Essential Oil from the Edible Aromatic Plant Aristolochia delavayi

The essential oil obtained by hydrodistillation from the aerial parts of Aristolochia delavayi Franch. (Aristolochiaceae), a unique edible aromatic plant consumed by the Nakhi (Naxi) people in Yunnan, China, was investigated using GC/MS analysis. In total, 95 components, representing more than 95% of the oil composition, were identified, and the main constituents found were (E)‐dec‐2‐enal (52.0%), (E)‐dodec‐2‐enal (6.8%), dodecanal (3.35%), heptanal (2.88%), and decanal (2.63%). The essential oil showed strong inhibitory activity (96% reduction) of the production of bacterial volatile sulfide compounds (VSC) by Klebsiella pneumoniae, an effect that was comparable with that of the reference compound citral (91% reduction). Moreover, the antimicrobial activity of the essential oil and the isolated major compound against eight bacterial and six fungal strains were evaluated. The essential oil showed significant antibacterial activity against Providencia stuartii and Escherichia coli, with minimal inhibitory concentrations (MIC) ranging from 3.9 to 62.5 μg/ml. The oil also showed strong inhibitory activity against the fungal strains Trichophyton ajelloi, Trichophyton terrestre, Candida glabrata, Candida guilliermondii, and Cryptococcus neoformans, with MIC values ranging from 3.9 to 31.25 μg/ml, while (E)‐dec‐2‐enal presented a lower antifungal activity than the essential oil.     

Synthesis,Cytotoxic, and Antibacterial Evaluation of Quinazolinone Derivatives with Substituted Amino Moiety

A series of novel quinazolinone derivatives containing a substituted amino moiety were synthesized, evaluated for their cytotoxic and antibacterial activities. The results of MTT assay showed that all synthesized target compounds 5A  –  5O showed potent cytotoxicity against SGC‐7901 (IC₅₀, 0.72 – 1.41 μm ). Moreover, the compounds 5D , 5I , and 5K showed better selectivity as compared with positive controls pemetrexed and MTX due to weak cytotoxicity against normal tissue cell line HUVSMC. Among synthesized compounds, the compounds 5E , 5J , 5L , and 5N showed broad‐spectrum cytotoxic activities against at least four cancer cell lines at a micromolar level. The results of antibacteria evaluation revealed that all synthesized compounds showed good to moderate antibacterial activities against Gram‐negative bacteria Escherichia coli. Among them, the MIC values of the compounds 5C , 5F , and 5M were 0.31 μg/mL.     

New Pyran‐2‐ones from Alkalophilic Actinomycete,Nocardiopsis alkaliphila sp. Nov. YIM‐80379

Two new pyran‐2‐ones, nocardiopyrones A and B ( 1 and 2 , resp.), along with four known compounds, pyridinols 3 – 5 , and 1‐acetyl‐β‐carboline ( 6 ) were isolated from the alkalophilic actinomycete Nocardiopsis alkaliphila sp. nov. YIM‐80379. Their structures were established on the basis of spectroscopic analysis, CD spectra, and the quantum‐chemical ECD calculation. Pyridinols 3 – 5 were isolated from a natural source for the first time. Compounds 1 and 2 showed weak antibacterial activities against Pseudomonas aeruginosa, Enterobacter aerogenes, and Escherichia coli with MIC values of 20–48 μM . Compound 2 showed weak antimicrobial activities against Candida albicans and Staphylococcus aureus with MIC values of 24 and 48 μM , respectively.     

Design,Synthesis, and Cholinesterase Inhibition Assay of Coumarin‐3‐carboxamide‐N‐morpholine Hybrids as New Anti‐Alzheimer Agents

A new series of coumarin‐3‐carboxamide‐N‐morpholine hybrids 5a – 5l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2‐hydroxybenzaldehyde derivatives and Meldrum's acid to afford corresponding coumarin‐3‐carboxylic acids. Then, amidation of the latter compounds with 2‐morpholinoethylamine or N‐(3‐aminopropyl)morpholine led to the formation of the compounds 5a – 5l . The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholine derivative 5g (N‐[3‐(morpholin‐4‐yl)propyl]‐2‐oxo‐2H‐chromene‐3‐carboxamide) bearing an unsubstituted coumarin moiety and ethylmorpholine derivative 5d (6‐bromo‐N‐[2‐(morpholin‐4‐yl)ethyl]‐2‐oxo‐2H‐chromene‐3‐carboxamide) bearing a 6‐bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of compound 5g against AChE was 1.78 times more than that of rivastigmine and anti‐BuChE activity of compound 5d is approximately same as rivastigmine. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.     

Sulfur‐Containing Ferrocenyl Alcohols and Oximes: New Promising Antistaphylococcal Agents

A small library containing four different series of new ferrocene derivatives, 2‐(alkylsulfanyl)‐1‐ferrocenylethan‐1‐ols, 3‐(alkylsulfanyl)‐1‐ferrocenylpropan‐1‐ols, (E)‐ and (Z)‐2‐(alkylsulfanyl)‐1‐ferrocenylethan‐1‐one oximes, and (E)‐ and (Z)‐3‐(alkylsulfanyl)‐1‐ferrocenylpropan‐1‐one oximes (36 different compounds in total) was synthesized starting from ferrocene and the corresponding sulfanyl acids. All compounds were spectrally (IR and NMR) and electrochemically characterized. In general, the obtained compounds were found to exhibit very strong antimicrobial activities (broth microdilution assay) against the tested microorganisms (six common human pathogens). For the majority of the tested compounds, the determined MIC values were either under the 10 μg/ml MIC limit recognized to delimit efficient antimicrobials or were comparable to/lower than those of the used positive controls (tetracycline/nystatin). The most susceptible organism was found to be Staphylococcus aureus with MIC values even reaching 0.001 μg/ml. The presence of ? CH(OH)(CH₂)_nS? and ? CH(?NOH)(CH₂)_nS? (n=1 or 2) structural fragments seems to be essential for the observed strong activity (introduction of hydroxyimino and alcohol functionalities, instead of the keto function, resulted in a more than 10⁵‐fold increase in antistaphylococcal activity in some instances). Nevertheless, a possible influence of the ferrocenyl‐core redox chemistry (Fe²⁺/Fe³⁺) should not be disregarded. The studied alcohols exhibited a reversible one‐electron redox couple at almost the same position as ferrocene, while the hydroxyimino group conjugated with cyclopentadienyl ring considerably shifted the redox potential of the ferrocene unit in oximes.     

Chemical Composition and Antimicrobial Activity of Ageratina deltoidea

The chemical study of Ageratina deltoidea afforded grandiflorenic acid ( 1 ), ent‐kaurenoic acid ( 2 ), and eight benzylbenzoates ( 3  –  10 ), two of them, 3,5‐dimethoxybenzyl 2,3,6‐trimethoxybenzoate ( 5 ) and 4‐(β‐d ‐glucopyranosyloxy)‐3‐hydroxybenzyl 2,6‐dimethoxybenzoate ( 9 ), described for the first time. In addition, the new sesquiterpene lactone deltoidin C ( 13 ), together with the known 11 and 12 , the phenolic compounds: ayanin, 2,6‐dimethoxybenzoic acid, methyl 3,4‐dihydroxycinnamate, chlorogenic acid, and 3,5‐dicaffeoylquinic acid were also isolated. The structures of these compounds were determined by spectroscopic methods and chemical reactions. The antibacterial and antifungal activities of compounds 1  –  12 were evaluated on Staphylococcus aureus, Escherichia coli, and Candida albicans. Deltoidin A ( 11 ) was the most active antibacterial agent (MIC 16.0 μg ml^?1) against E. coli, and the ent‐kaurenoid derivatives ( 1  –  2 ) showed activity (MIC 31.0 μg ml^?1) against S. aureus.     

Activities of Wogonin Analogs and Other Flavones against Flavobacterium columnare

In our on‐going pursuit to discover natural products and natural product‐based compounds to control the bacterial species Flavobacterium columnare, which causes columnaris disease in channel catfish (Ictalurus punctatus), we synthesized flavone and chalcone analogs, and evaluated these compounds, along with flavonoids from natural sources, for their antibacterial activities against two isolates of F. columnare (ALM‐00‐173 and BioMed) using a rapid bioassay. The flavonoids chrysin ( 1a ), 5,7‐dihydroxy‐4′‐methoxyflavone ( 11 ), isorhamnetin ( 26 ), luteolin ( 27 ), and biochanin A ( 29 ), and chalcone derivative 8b showed strong antibacterial activities against F. columnare ALM‐00‐173 based on minimum inhibition concentration (MIC) results. Flavonoids 1a, 8, 11, 13 (5,4′‐dihydroxy‐7‐methoxyflavone), 26 , and 29 exhibited strong antibacterial activities against F. columnare BioMed based upon MIC results. The 24‐h 50% inhibition concentration (IC₅₀) results revealed that 27 and 29 were the most active compounds against F. columnare ALM‐00‐173 (IC₅₀ of 7.5 and 8.5 mg/l, resp.), while 26 and 29 were the most toxic compound against F. columnare BioMed (IC₅₀ of 9.2 and 3.5 mg/l, resp.). These IC₅₀ results were lower than those obtained for wogonin against F. columnare ALM‐00‐173 and F. columnare BioMed (28.4 and 5.4 mg/l, resp.). However, based on MIC results, none of the compounds evaluated in this study were as active as wogonin (MIC 0.3 mg/l for each F. columnare isolate). Further modification of the wogonin structure to enhance antibacterial is of interest.     

In vitro Growth Inhibition by Hypericum Extracts and Isolated Pure Compounds of Paenibacillus larvae,a Lethal Disease Affecting Honeybees Worldwide

The in vitro inhibitory potential of 50 extracts from various species of the flowering plant genus Hypericum was investigated using the Kirby? Bauer disk diffusion susceptibility test against Paenibacillus larvae, a spore‐forming, Gram‐positive bacterial pathogen that causes American foulbrood (AFB), a lethal disease affecting honeybee brood worldwide. Of the tested extracts, 14 were identified as highly active against P. larvae as compared to the activity of the positive control, indicating the presence of highly potent antibacterial compounds in the extracts. Examination of these extracts using TLC and HPLC/MS analyses revealed the presence of acylphloroglucinol and filicinic‐acid derivatives. Six pure compounds isolated from these extracts, viz., hyperforin ( 1 ), uliginosin B ( 2 ), uliginosin A ( 3 ), 7‐epiclusianone ( 4 ), albaspidin AA ( 5 ), and drummondin E ( 6 ), displayed strong antibacterial activity against the vegetative form of P. larvae (MIC ranging from 0.168–220 μM ). Incubation of P. larvae spores with the lipophilic extract of Hypericum perforatum and its main acylphloroglucinol constituent 1 led to the observation of significantly fewer colony forming units as compared to the negative control, indicating that the acylphloroglucinol scaffold represents an interesting lead structure for the development of new AFB control agents.     

Design,synthesis, spectral analysis and in vitro microbiological evaluation of 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones

A series of novel 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones 23-33 were synthesized, and studied for their in vitro antibacterial and antifungal activities against clinically isolated strains. Generally compounds possessing electron donating groups showed good antibacterial activity. Compound 31, which contain both electron withdrawing chloro and electron donating methyl groups showed potent activity against all the tested Gram positive and Gram negative bacterial strains whereas compounds 32 and 33 which contain electron donating methoxy functional group at the para position of the phenyl ring attached to pyrimidine ring showed promising activity against S.aureus, S.typhii and E.coli. Compounds 32 and 33, both containing electron withdrawing groups (-Cl, -F) showed excellent activities against all the tested A. flavus, Mucor, Rhizopus and M.gypsuem fungal strains. while against Mucor, compound 27 which contains an electron donating methyl group at the para position of the phenyl ring attached to pyrimidine ring showed promising activity. Also compound 31, which contains both electron withdrawing chloro and electron donating methyl groups showed potent activity against A. flavus and Rhizopus.     

Chemical Composition and Antifungal Activity of the Essential Oils of Lavandula pedunculata (Miller) Cav.

The chemical composition and antifungal activity of the essential oils of Lavandula pedunculata (Miller ) Cav. , harvested in North and Central Portugal, were investigated. The essential oils were isolated by hydrodistillation and analyzed by GC and GC/MS. The minimal‐inhibitory concentration (MIC) and the minimal‐lethal concentration (MLC) of the essential oils and of their major constituents were used to evaluate the antifungal activity against different strains of fungi involved in candidosis, dematophytosis, and aspergillosis. The oils were characterized by a high percentage of oxygenated monoterpenes, the main compounds being 1,8‐cineole (2.4–55.5%), fenchone (1.3–59.7%), and camphor (3.6–48.0%). Statistical analysis differentiated the essential oils into two main types, one characterized by the predominance of fenchone and the other one by the predominance of 1,8‐cineole. Within the 1,8‐cineole chemotype, two subgroups were well‐defined taking into account the percentages of camphor. A significant antifungal activity of the oils was found against dermatophyte strains. The essential oil with the highest content of camphor was the most active with MIC and MLC values ranging from 0.32–0.64 μl/ml.     

Azaphilones from the Fungus Penicillium multicolor LZUC-S2 and Their Antibacterial Activity

Two new azaphilones, penimultiones A and B, together with seven known analogs were isolated from the culture of Penicillium multicolor LZUC-S2. Their structures were elucidated by detailed spectroscopic data analysis and chemical transformation. Penimultiones A and B belong to a rare class of azaphilones possessing a 1,3-dioxolane moiety. In addition, all compounds were evaluated for their antibacterial activity against five clinically bacterial strains in vitro, and three compounds showed potent antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 12.5 to 50.0 μg/mL.     

Synthesis,Antimicrobial Activities,and Molecular Docking Studies of Dihydrotriazine Derivatives Bearing a Quinoline Moiety

In this article, three series of dihydrotriazine derivatives bearing a quinoline moiety ( 5a , 5b , 8a – 8c , and 9a – 9m ) have been designed, synthesized, and evaluated as antibacterial agents. Compounds 8a – 8c were found to be the most potent of all of the compounds tested with an MIC value of 1 μg/mL against several Gram‐positive (S. aureus 4220 and MRSA CCARM 3506) and Gram‐negative (E. coli 1924) strains of bacteria. In addition, 3‐[4‐amino‐6‐(phenethylamino)‐2,5‐dihydro‐1,3,5‐triazin‐2‐yl)‐6‐[(3‐chlorobenzyl)oxy]quinolin‐2‐ol ( 8a ) showed potent inhibitory activity (MIC=2 μg/mL) against Pseudomonas aeruginosa 2742, indicating that its antibacterial spectrum is similar to those of the positive controls gatifloxacin and moxifloxacin. Structure‐activity relationships (SAR) analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency of the quinoline compounds. In vitro enzyme study implied that compound 8a also displayed DHFR inhibition.     

Sesquiterpenoids with Anti‐MDR Staphylococcus aureus Activities from Ferula ferulioides

Seven new sesquiterpenoids together with 21 known sesquiterpenoid derivatives were isolated from the medicinal plant Ferula ferulioides (Steud .) Korovin . Their structures were elucidated by comprehensive spectroscopic analyses and chemical transformations. The isolated compounds were evaluated for their antibacterial activities against a panel of bacteria including multidrug‐resistant (MDR) and methicillin‐resistant Staphylococcus aureus (MRSA), displaying minimum inhibitory concentration (MIC) values in the range of 0.5–128 mg/l.     

Synthesis and biological evaluation of 5-aryloxypyrazole derivatives bearing a rhodanine-3-aromatic acid as potential antimicrobial agents

Three novel series of 5-aryloxypyrazole derivatives have been synthesized and tested for their antibacterial activity. The majority of the synthesized compounds showed potent inhibitory activity against Gram-positive bacteria Staphylococcus aureus 4220, especially against the strains of multidrug-resistant clinical isolates (MRSA3167/3506 and QRSA3505/3519). Among which compounds IIIb, IIIg and IIIm showed the most potent levels of activity (MIC = 1 μg/mL) against the multidrug-resistant strains. And cytotoxic activity assay showed that the compounds tested did not affect cell viability on the Human cervical (HeLa) cells at their MICs. The current study therefore suggests that 5-aryloxypyrazoles bearing a rhodanine-3-aromatic acid moiety are promising scaffolds for the development of novel Gram-positive antibacterial agents.     

Anti‐Inflammatory Effect of Novel 7‐Substituted Coumarin Derivatives through Inhibition of NF‐κB Signaling Pathway

A series of novel 7‐substituted coumarin derivatives were synthesized and evaluated. Biological screening results obtained by the evaluation of the compounds’ inhibition against LPS‐induced IL‐6 and TNF‐α release in RAW 264.7 cells indicated that most compounds exhibited potent anti‐inflammatory activity. Among them, N‐(3‐methoxybenzyl)‐2‐[(2‐oxo‐2H‐chromen‐7‐yl)oxy]acetamide ( 2d ) showed the best activity. The potential targets of title compound 2d were reversely screened with the molecular modeling software, Discovery Studio 2017 R2. Screening and molecule docking results showed that 2d could bind to the active site (NLS Polypeptide) of NF‐κB p65, and this binding affinity was confirmed by surface plasmon resonance (SPR) analysis. Furthermore, Western blot assay showed that 2d remarkably blocked the NF‐κB signaling pathway in vitro. Collectively, all these findings suggested that compound 2d might be a promising lead compound worthy of further pursuit.     

Exploration of Phytoconstituents from Mussaenda roxburghii and Studies of Their Antibiofilm Effect

In the context of ethno botanical importance with no phytochemical investigations, Mussaenda roxburghii have been investigated to explore it's phytoconstituents and studies of their antibiofilm activity. Four compounds have been isolated from the aerial parts of this plant and were characterized as 2α,3β,19α,23‐tetrahydroxyurs‐12‐en‐28‐oic acid ( 1 ), β‐sitosterol glucoside ( 4 ), lupeol palmitate ( 5 ), and myoinositol ( 6 ). All these compounds were tested for antibacterial and antibiofilm activity against Pseudomonas aeruginosa. Compound 1 exhibited three times more antibiofilm activity with minimum inhibitory concentration (MIC) at 0.74 mm compared to that of streptomycin. Molecular docking studies exhibited a very high binding affinity of 1 with P. aeruginosa quorum sensing proteins and motility associated proteins viz. LasR and PilB, PilY1, PilT, respectively. Compound 1 was also found to be non‐cytotoxic against sheep RBC and murine peritoneal macrophages at selected sub‐MIC doses.     

Antibacterial Activity of Enrofloxacin and Ciprofloxacin Derivatives of β‐Octaarginine

β³‐Octaarginine chains were attached to the functional groups NH and CO₂H of the antibacterial fluoroquinolones ciprofloxacin (→ 1 ) and enrofloxacin (→ 2 ), respectively, in order to find out whether the activity increases by attachment of the polycationic, cell‐penetrating peptide (CPP) moiety. For comparison, simple amides, 3 – 5 , of the two antimicrobial compounds and β³‐octaarginine amide ( βR₈ ) were included in the antibacterial susceptibility tests to clarify the impact of chemical modification on the microbiological activity of either scaffold (Table).     

Hydrazones of 2-aryl-quinoline-4-carboxylic acid hydrazides: synthesis and preliminary evaluation as antimicrobial agents

A new series of 2-arylquinoline-4-carboxylic acid hydrazide–hydrazones was synthesized using an appropriate synthetic route. All the target compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus as an example for Gram-positive bacteria, Escherichia coli as an example for Gram-negative bacteria, and Candida albicans as a representative of fungi. The minimum inhibitory concentration (MIC) was determined for test compounds as well as for reference standards. Among the compounds tested, compounds having nitro substituents at the arylidene moiety showed the most potent antifungal as well as antibacterial activities against E. coli. Compound 23 displayed an antifungal activity comparable to that of nystatin. However, none of the compounds demonstrated any antibacterial activity against S. aureus. Hydrophobicity of the target compounds correlated weakly with their antibacterial and antifungal activities. The most potent compounds namely, 7, 18, 19, 22, and 23 were assessed for hemolytic toxicity and found to be non-hemolytic up to a concentration of 100 μg/mL. In addition, the most potent compound (23) was evaluated for in vitro cytotoxic activity against various cancer cell lines. This compound was found to display no cytotoxic activity but rather it induces the proliferation rate of Hep-G2 cells.