Antimycobacterial activity of salicylanilide benzenesulfonates

A series of eighteen novel esters of salicylanilides with benzenesulfonic acid were designed, synthesized and characterized by IR, 1H-NMR and 13C-NMR. They were evaluated in vitro as potential antimycobacterial agents towards Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. In general, the minimum inhibitory concentrations range from 1 to 500 μmol/L. The most active compound against M. tuberculosis was 4-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)-phenyl benzenesulfonate, with MIC of 1 μmol/L and towards M. kansasii its isomer 5-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl benzenesulfonate (MIC of 2-4 μmol/L). M. avium was the less susceptible strain. However, generally, salicylanilide benzenesulfonates did not surpass the activity of other salicylanilide esters with carboxylic acids.     

An effective method for the synthesis of carboxylic esters and lactones using substituted benzoic anhydrides with Lewis acid catalysts

An efficient mixed-anhydride method for the synthesis of carboxylic esters and lactones using benzoic anhydride having electron withdrawing substituent(s) is developed by the promotion of Lewis acid catalysts. In the presence of a catalytic amount of TiCl₂(ClO₄)₂, various carboxylic esters are prepared in high yields through the formation of the corresponding mixed-anhydrides from 3,5-bis(trifluoromethyl)benzoic anhydride and carboxylic acids. The combined catalyst consisting of TiCl₂(ClO₄)₂ together with chlorotrimethylsilane functions as an effective catalyst for the synthesis of carboxylic esters from free carboxylic acids and alcohols with 4-(trifluoromethyl)benzoic anhydride. Various macrolactones are prepared from the free ω-hydroxycarboxylic acids by the combined use of 4-(trifluoromethyl)benzoic anhydride and titanium(IV) catalysts together with chlorotrimethylsilane under mild reaction conditions. The lactonization of trimethylsilyl ω-(trimethylsiloxy)carboxylates using 4-(trifluoromethyl)benzoic anhydride is also promoted at room temperature in the presence of a catalytic amount of TiCl₂(ClO₄)₂. An 8-membered ring lactone, a synthetic intermediate of cephalosporolide D, is successfully synthesized according to this mixed-anhydride method using 4-(trifluoromethyl)benzoic anhydride by the promotion of a catalytic amount of Hf(OTf)₄.     

Phenolic glucosides and chromane analogs from the insect fungus Conoideocrella krungchingensis BCC53666

Six new compounds, named conoideoglucosides A − C and conoideochromanes A − C, together with eight known compounds, including eutypinic acid, 2,2-dimethyl-2H-1-chromene-6-carboxylic acid, (−)-luteoskyrin, (−)-4a-oxyluteoskyrin, chrysophanol, islandicin, catenarin, and (22E)-5α,8α-epidioxyergosta-6,22-dien-3β-ol were isolated from the insect fungus Conoideocrella krungchingensis BCC53666. (−)-Luteoskyrin exhibited a broad range of antimicrobial activity such as antimalarial (IC₅₀ 0.51 μg/mL), antitubercular (MIC 6.25 μg/mL), antibacterial (both Gram positive; MIC 0.39–1.56 μg/mL and Gram negative; MIC 3.13–12.50 μg/mL), and antifungal (against various plant pathogens; MIC 3.13–50.00 μg/mL) activities, while (−)-4a-oxyluteoskyrin and catenarin showed weaker antibacterial activity. Moreover, eutypinic acid, (−)-luteoskyrin, (−)-4a-oxyluteoskyrin, and catenarin showed cytotoxicity against NCI-H187 cells with IC₅₀ in a range of 0.16–17.99 μg/mL, while eutypinic acid and catenarin had no cytotoxicity against non-cancerous (Vero) cells at maximum tested concentration (50 μg/mL). The complete NMR spectral data and biological activity of the known (−)-4a-oxyluteoskyrin was also reported for the first time.     

Synthesis, antimycobacterial, antifungal and photosynthesis-inhibiting activity of chlorinated N-phenylpyrazine-2-carboxamides

A series of sixteen pyrazinamide analogues with the -CONH- linker connecting the pyrazine and benzene rings was synthesized by the condensation of chlorides of substituted pyrazinecarboxylic acids with ring-substituted (chlorine) anilines. The prepared compounds were characterized and evaluated for their antimycobacterial and antifungal activity, and for their ability to inhibit photosynthetic electron transport (PET). 6-Chloro-N-(4-chlorophenyl)pyrazine-2-carboxamide manifested the highest activity against Mycobacterium tuberculosis strain H37Rv (65% inhibition at 6.25 μg/mL). The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 6-chloro-5-tert-butyl-N-(3,4-dichlorophenyl)pyrazine-2-carboxamide (MIC=62.5 μmol/L). 6-chloro-5-tert-butyl-N-(4-chlorophenyl)pyrazine-2-carboxamide showed the highest PET inhibition in spinach chloroplasts (Spinacia oleracea L.) chloroplasts (IC50=43.0 μmol/L). For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structure-activity relationships are discussed.     

A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in amidoalkylation of hydrogen,heteroatom, and carbon nucleophiles

A general synthesis of previously unknown semicarbazone-based α-amidoalkylating reagents, 4-(tosylmethyl)semicarbazones, has been developed. The synthesis involved three-component condensation of semicarbazones of aliphatic or aromatic aldehydes with the same or other aldehydes and p-toluenesulfinic acid. The scope and limitations of this reaction were investigated. The compounds obtained were demonstrated to be an efficient α-(4-semicarbazono)alkylating agents. They were reacted with H- (sodium borohydride), O- (sodium methylate), S- (sodium phenylthiolate), N- (pyrrolidine, sodium succinimide), P- (trialkyl phosphites), and C-nucleophiles (sodium diethyl malonate) to give the corresponding products of the tosyl group substitution, 4-substituted semicarbazones, including analogues of nitrofurazone. Among the prepared compounds tested in vitro for antibacterial and antifungal activity, three nitrofuryl-containing semicarbazones exhibited high biological activities with minimum inhibitory concentration (MIC) values of 8–32 μg/mL.     

Structural studies of palladium complexes with ligands containing the amide group

Summary Complexes of palladium(II) with 2-(acetylamino)benzoic acid, 2-(benzoylamino)benzoic acid, 2-[2-aminobenzoylamino]benzoic acid, 2-hydroxy benzanilide, 2-mercapto benzanilide, maleanilic acid, 2-(amino carbonyl)benzoic acid, 2-[(phenylamino)carbonyl]benzoic acid, 2-[(1-naphthalenylamino)carbonyl]benzoic acid, 2-[(2-aminophenylamino)carbonyl]benzoic acid, salicylanilide, 2-(aminobenzoyl)benzoic acid and 2-aminobenzamide have been prepared and characterized by chemical analyses, molar conductivity measurements, thermal data and i.r., electronic and n.m.r. spectra.     

An unprecedented rearrangement of salicylanilide derivatives: imidazolinone intermediate formation

The preparation of new prodrug forms of anti-tuberculosis active salicylanilide esters with amino acids led to an unexpected rearrangement. The isolation and the structure determination of 2-(5-chloro-2-hydroxyphenyl)-3-(3-chlorophenyl)-5-substituted-3,5-dihydro-4H-imidazol-4-ones unambiguously confirm one of the two proposed reaction mechanisms.     

Spectrophotometric quantification of the salicylanilide anthelmintic rafoxanide based on the charge-transfer absorbance of its iron(III) complex

Formation of an iron(III)—rafoxanide chelate provides the basis for a direct spectrophotometric method for the quantification of this halogenated salicylanilide in the concentration range 9.00 × 10^-4–7.00 × 10^-3 M. The intense visible charge-transfer absorption band of the complex at 505 nm represents a general spectrophotometric characteristic that is useful for other substituted salicylanilides. The maximum absorption wavelength of the charge-transfer band shifts monotonically to higher energy in an order consistent with Hammett substituent constants.     

A simple and convenient synthesis of 3-[5-(trifluoromethyl)-1,2,3-triazol-4-yl]cinnamic acids from 4-aryl-6-(trifluoromethyl)-2H-pyran-2-ones and sodium azide

4-Aryl-6-(trifluoromethyl)-2H-pyran-2-ones and ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-3-carboxylates react with sodium azide to produce highly functionalized CF₃-1,2,3-triazoles: 3-[5-(trifluoromethyl)-1,2,3-triazol-4-yl]cinnamic acids and monoethyl esters of [5-(trifluoromethyl)-1,2,3-triazol-4-yl]arylmethylidene malonic acids.     

Indole-derived chalcones as anti-dermatophyte agents: In vitro evaluation and in silico study

A series of indole-derived methoxylated chalcones were described as anti-dermatophyte agents. The in vitro antifungal susceptibility testing against different dermatophytes revealed that most of compounds had potent activity against the dermatophyte strains. In particular, the 4-ethoxy derivative 4d with MIC values of 0.25−2 μg/ml was the most potent compound against Trichophyton interdigitale, Trichophyton veruccosum and Microsporum fulvum. Moreover, the 4-butoxy analog 4i displaying MIC values in the range of 1−16 μg/ml had the highest inhibitory activity against Trichophyton mentagrophytes, Microsporum canis, and Arthroderma benhamiae. To predict whether the synthesized compounds interact with tubulin binding site of dermatophytes, the 3D-structure of target protein was modeled by homology modeling and then used for molecular docking and molecular dynamics (MD) simulation studies. Docking simulation revealed that the promising compound 4d can properly bind with tubulin. The molecular dynamics analysis showed that interactions of compound 4d with the active site of target protein have binding stability throughout MD simulation. The results of this study could utilize in the design of more effective antifungal drugs with tubulin inhibition mechanism against keratinophilic fungi.     

Niclosamide Is Active In Vitro against Mycetoma Pathogens

Redox-active drugs are the mainstay of parasite chemotherapy. To assess their repurposing potential for eumycetoma, we have tested a set of nitroheterocycles and peroxides in vitro against two isolates of Madurella mycetomatis, the main causative agent of eumycetoma in Sudan. All the tested compounds were inactive except for niclosamide, which had minimal inhibitory concentrations of around 1 µg/mL. Further tests with niclosamide and niclosamide ethanolamine demonstrated in vitro activity not only against M. mycetomatis but also against Actinomadura spp., causative agents of actinomycetoma, with minimal inhibitory concentrations below 1 µg/mL. The experimental compound MMV665807, a related salicylanilide without a nitro group, was as active as niclosamide, indicating that the antimycetomal action of niclosamide is independent of its redox chemistry (which is in agreement with the complete lack of activity in all other nitroheterocyclic drugs tested). Based on these results, we propose to further evaluate the salicylanilides, niclosamide in particular, as drug repurposing candidates for mycetoma.     

Determination of hydroxyl radical by capillary electrophoresis and studies on hydroxyl radical scavenging activities of Chinese herbs

High-performance capillary electrophoresis (CE) with electrochemical detection (ED) was employed to determine hydroxyl radicals in the Fenton reaction. Hydroxyl radicals can react with salicylic acid to produce 2,3-dihydroxy benzoic acid and 2,5-dihydroxy benzoic acid, which can be analyzed by CE-ED. Based on this principle, hydroxyl radicals were determined indirectly. In a 20 mmol/L phosphate running buffer (pH 7.4), 2,3-dihydroxy benzoic acid and 2,5-dihydroxy benzoic acid would elute simultaneously from the capillary within 6 min. As the working electrode, a 300 m diameter carbon-disk electrode exhibits good responses at +0.60 V (vs. SCE) for the two analytes. Peak currents of the two analytes are additive. Excellent linearity was obtained in the concentration range from 1.0×10^-3 mol/L to 5.0×10^-6 mol/L for 2,3-dihydroxy benzoic acid. The detection limit (S/N=3) was 2.0×10^-6 mol/L. This method was successfully applied for studying hydroxyl radical scavenging activities of Chinese herbs. It is testified that Apocynum Venetum L., Jinkgo bibola L., Morus alba L. and Rhododendron dauricum L. have strong hydroxyl radical scavenging activities.     

反相高效液相色谱法测定化妆品中的苯甲酸和山梨酸

建立了反相高效液相色谱法测定化妆品中苯甲酸和山梨酸的分析方法.样品经甲醇超声提取后,直接过滤进样检测.采用Sinochrom C18色谱柱,以0.02 mol/L乙酸铵-甲醇(体积比为85:15)为流动相,流速为2.0 mL/min,检测波长为230 nm.结果表明:苯甲酸和山梨酸浓度在2.00～12.00 μg/mL...     

Novel Galactopyranoside Esters: Synthesis,Mechanism, In Vitro Antimicrobial Evaluation and Molecular Docking Studies

One-step direct unimolar valeroylation of methyl α-D-galactopyranoside (MDG) mainly furnished the corresponding 6-O-valeroate. However, DMAP catalyzed a similar reaction that produced 2,6-di-O-valeroate and 6-O-valeroate, with the reactivity sequence as 6-OH > 2-OH > 3-OH,4-OH. To obtain novel antimicrobial agents, 6-O- and 2,6-di-O-valeroate were converted into several 2,3,4-tri-O- and 3,4-di-O-acyl esters, respectively, with other acylating agents in good yields. The PASS activity spectra along with in vitro antimicrobial evaluation clearly indicated that these MDG esters had better antifungal activities than antibacterial agents. To rationalize higher antifungal potentiality, molecular docking was conducted with sterol 14α-demethylase (PDB ID: 4UYL, Aspergillus fumigatus), which clearly supported the in vitro antifungal results. In particular, MDG ester 7–12 showed higher binding energy than the antifungal drug, fluconazole. Additionally, these compounds were found to have more promising binding energy with the SARS-CoV-2 main protease (6LU7) than tetracycline, fluconazole, and native inhibitor N3. Detailed investigation of Ki values, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and the drug-likeness profile indicated that most of these compounds satisfy the drug-likeness evaluation, bioavailability, and safety tests, and hence, these synthetic novel MDG esters could be new antifungal and antiviral drugs.     

Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial agents

A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains(including multidrug-resistant clinical isolates) and Gramnegative bacterial strains, with minimum inhibitory concentrations(MICs) in the range of 2.1–181.2 mmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Grampositive bacteria(e.g., Staphylococcus aureus 4220), Gram-negative bacteria(e.g., Escherichia coli 1924),and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1 mmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1 mmol/L against four multidrug-resistant, Gram-positive bacterial strains.The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.     

Development of a simple HPLC–MS/MS method to simultaneously determine teriflunomide and its metabolite in human plasma and urine: Application to clinical pharmacokinetic study of teriflunomide sodium and leflunomide

A simple high‐performance liquid chromatography coupled with tandem mass spectrometry method was developed and fully validated to simultaneously determine teriflunomide (TER) and its metabolite 4‐trifluoro‐methylaniline oxanilic acid (4‐TMOA) in human plasma and urine. Merely 50 μL plasma and 20 μL urine were employed in sample preparation using protein precipitation and direct dilution method, respectively. An Agilent Zorbax eclipse plus C₁₈ column was selected to achieve rapid separation for TER and 4‐TMOA within 3 min. Electrospray ionization under multiple reaction monitoring was used to monitor the ion transitions for TER (m/z 269.0 → 159.9), 4‐TMOA (m/z 231.9 → 160.0), internal standard teriflunomide‐d4 (m/z 273.0 → 164.0) and 2‐amino‐4‐trifluoromethyl benzoic acid (m/z 203.8 → 120.1), operating in the negative ion mode. This method proved to have better accuracy and precision over concentration range of 10–5000 ng/mL in plasma as well as 10–10,000 ng/mL in urine. After a full validation, this method was successfully applied in a pharmacokinetic study of teriflunomide sodium and leflunomide in Chinese healthy volunteers.     

KBrO3—KBr紫外分光光度法测定痕量水杨酸

研究了ＨＣｌ溶液中ＫＢｒＯ３－ＫＢｒ紫外分光光度法测定水杨酸的条件,建立了测定痕量水杨酸的新方法。结果表明,在０．６ｍｏｌ／ＬＨＣｌ,３＊１０＾－５ｍｏｌ／ＬＫＢｒＯ３,５＊１０＾－４ｍｏｌ／ＬＫＢｒ,６＊１０＾－４ｍｏｌ／ｌＫＩ溶中测定水杨酸,其线性范围为０．２－４．０ｍｇ／Ｌ,表观摩尔吸光系数为１．９＊１０＾－４Ｌ．ｍｏｌ＾－１．ｃｍ＾－１,Ｓａｎｄｅｌｌ为７．３μｇ／ｃｍ＾２。ｓｇ ｉｆ ｅ     

Cereusitin A,a cyclic tetrapeptide from a Bacillus cereus strain isolated from the soft coral Antillogorgia (syn. Pseudopterogorgia) elisabethae

Two new compounds, cereusitin A (1), the tetrapeptide cyclo-(L-phenylalanyl-trans-4-hydroxy-L-prolyl-L-leucyl-trans-4-hydroxy-L-proline and 4-(R)-hydroxysattabacin (2), along with the methyl, isopropyl, and propyl esters of p-hydroxybenzoic acid (3–5) were isolated from the organic extracts of the culture of the B. cereus RKHC-09 strain in two culture media (MOLP and B1), recovered from the sea fan Antillogorgia elisabethae (syn. Pseudopterogorgia elisabethae). Cereusitin A (1) showed mild antifungal activity against Colletotrichum gloeosporoides C26 (yam pathogen) but was inactive against Fusarium oxysporum f.sp. dianthi (carnation pathogen). The methyl and propyl esters of p-hydroxybenzoic acid (4 and 5) showed antimicrobial activity against S. aureus ATCC 33591 and S. cerevisiae, with an MIC of 2 μM.     

Chromenol Derivatives as Novel Antifungal Agents: Synthesis,In Silico and In Vitro Evaluation

Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a–3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity with computer program PASS indicate that the compounds have a high novelty compared to the known antifungal agents. We did not find any close analog among the over 580,000 pharmaceutical agents in the Cortellis Drug Discovery Intelligence database at the similarity cutoff of 70%. The evaluation of antifungal activity in vitro revealed that the highest activity was exhibited by compound 3k, followed by 3n. Their MIC values for different fungi were 22.1–184.2 and 71.3–199.8 µM, respectively. Twelve from fourteen tested compounds were more active than the reference drugs ketoconazole and bifonazole. The most sensitive fungus appeared to be Trichoderma viride, while Aspergillus fumigatus was the most resistant one. It was found that the presence of the 2-(tert-butyl)-2H-chromen-2-ol substituent on the 4th position of the triazole ring is very beneficial for antifungal activity. Molecular docking studies on C. albicans sterol 14α-demethylase (CYP51) and DNA topoisomerase IV were used to predict the mechanism of antifungal activities. According to the docking results, the inhibition of CYP51 is a putative mechanism of antifungal activity of the novel chromenol derivatives. We also showed that most active compounds have a low cytotoxicity, which allows us to consider them promising antifungal agents for the subsequent testing activity in in vivo assays.     

Heteroleptic transition metal complexes of Schiff‐base‐derived ligands exert their antifungal activity by disrupting membrane integrity

Development of new treatment strategies and chemotherapeutic agents is urgently needed to combat the growing multidrug resistant species of Candida. In this direction, a new series of Cu (II), Co (II), Ni (II) and Zn (II) heteroleptic complexes were synthesized, characterized and evaluated for antifungal activity. Based on spectral characterization and physical measurements, an octahedral geometry was assigned to [Co(L1)(L2)ClH₂O] ( C2 ), [Ni(L1)(L2)ClH₂O] ( C3 ), [Zn(L1)(L2)ClH₂O] ( C4 ) complexes, while a distorted octahedral geometry was assigned to [Cu(L1)(L2)ClH₂O] ( C1 ) complex. All the synthesized compounds were tested for antifungal activity against 11 Candida albicans isolates, including fluconazole (FLC)‐resistant isolates, by determining minimum inhibitory concentrations (MIC) and minimum fungicidal concentrations (MFC), following CLSI guidelines. The mechanism of their antifungal activity was assessed by studying their effect on the plasma membrane using flow cytometry and quantifying the ergosterol contents. All the test compounds showed varying levels of antifungal activity. Both the ligands showed moderate antifungal activity with a median MIC value of 100 μg/mL with no fungicidal activity. Compound C3 was the most potent compound with median MIC and MFC values of 0.10 and 1.60 μg/mL, respectively. Flow cytometry analysis revealed that these compounds at MFC values disrupt the cell membrane, resulting in propidium iodide entering the cells. These compounds also reduced a considerable amount of ergosterol content after treating the cells with MIC and sub‐MIC values. This study indicates that these compounds have high antifungal activity against C. albicans, and have the potential to be developed as novel antifungal drugs.