Design,synthesis and antifungal evaluation of borrelidin derivatives

Borrelidin, a nitrile containing 18-membered polyketide macrolide, display potent antifungal activity. In this study, a library of borrelidin derivatives were synthesized. Their structures were elucidated by detailed spectroscopic data analysis. The antifungal activity and cytotoxicity of these target compounds were evaluated by broth microdilution and 3-(4,5-dimethylthiazol-2-yl)-3,5-phenytetrazoliumromide (MTT) methods. Among forty-seven prepared analogues, compound 3b had the inhibitory effect on Candida albicans and Candida parapsilosis (MIC: 50 and 12.5?μg/mL, respectively). Furthermore, compounds 4n and 4r presented better antifungal activity against Aspergillus fumigatus with 12.5?μg/mL MIC value, which were insensitive to borrelidin. Preliminary structure-activity relationships (SAR) revealed that the ester analogues containing fragment -OCH₂CH₂N- had an important effect on the antifungal activity. Meanwhile, the molecular docking study indicated the carboxyl substituents in BN could provide extra interaction with pathogenic fungal threonyl-tRNA synthetase (ThrRS).     

Total synthesis and biological evaluation of methylgerambullone

First total synthesis of methylgerambullone (MGB, 1) isolated from Glycosmis angustifolia was completed via a convergent route. The effect of MGB on the contractile responses of the isolated guinea-pig ileum induced by acetylcholine was investigated. As a result, it showed a potent relaxation rate (78.66 ± 4.30% at 100 mg/L) in a concentration-dependent manner on longitudinal smooth muscle contraction of isolated guinea-pig ileum induced by 1 μM acetylcholine.     

Design,synthesis and antifungal activity evaluation of isocryptolepine derivatives

In this paper, the nitrogen atom was inserted into the anthracycline system of the isocryptolepine nucleus to obtain the “Aza”-type structure benzo[4,5]imidazo[1,2-c] quinazoline. A series of “Aza”-type derivatives were designed, synthesized and evaluated for their antifungal activity against six plant fungi in vitro. Among all derivatives, compounds A-0, B-1 and B-2 showed significant antifungal activity against B. cinerea with the EC₅₀ values of 2.72 μg/mL, 5.90 μg/mL and 4.00 μg/mL, respectively. Compound A-2 had the highest activity against M. oryzae with the EC₅₀ values of 8.81 μg/mL, and compound A-1 demonstrated the most control efficacy against R. solani (EC₅₀, 6.27 μg/mL). Moreover, compound A-0 was selected to investigate the in vivo tests against B. cinerea and the results indicated that the preventative efficacy of it up to 72.80% at 100 μg/mL. Preliminary mechanism studies revealed that after treatment with A-0 at 5 µg/mL, the B. cinerea mycelia appeared curved, collapsed and the cell membrane integrity may be damaged. The reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia have been changed, and the membrane function and cell proliferation of mycelia were destroyed. Compounds A-0, A-1, B-1 and B-2 presented weaker toxicities against two cells lines than isocryptolepine. This study lays the foundation for the future development of isocryptolepine derivatives as environmentally friendly and safe agricultural fungicides.     

Total synthesis and biological evaluation of spirotryprostatin A analogs

Based on the spirotryprostatin A structure, a series of compounds belonging to spiro‐indolyl diketopiperazine structural class were designed and synthesized, which embody an oxindole with an all‐carbon quaternary stereocenter. The total synthesis can efficiently be accessed in a seven‐step reaction sequence with 18–28% overall yield from commercially available materials, and a highly enantioselective 1,3‐dipolar cycloaddition, N ‐acylation of the resulting stereochemically complex spiro[pyrrolidin‐3,3′‐oxindole]s core with Fmoc‐L ‐pro‐Cl and spontaneous ring closure upon N ‐deprotection were obtained. The synthesized compounds 13a–e and 15a–e were evaluated for their antibacterial activities. The result showed that compounds 13b and 15b were active only against Gram‐positive bacteria, and selective antibacterial activity was exhibited by compounds 13d and 13e against Streptococcus lactis . Further, all the remaining compounds showed a certain degree of antibacterial activity. In addition, the structure–activity relationship is also discussed.     

Design,synthesis, and in vitro evaluation of novel antifungal triazoles

Twenty-nine novel triazole analogues of ravuconazole and isavuconazole were designed and synthesized. Most of the compounds exhibited potent in vitro antifungal activities against 8 fungal isolates. Especially, compounds a10, a13, and a14 exhibited superior or comparable antifungal activity to ravuconazole against all the tested fungi. Structure-activity relationship study indicated that replacing 4-cyanophenylthioazole moiety of ravuconazole with fluorophenylisoxazole resulted in novel antifungal triazoles with more effectiveness and a broader-spectrum.     

Total synthesis and cytotoxicity evaluation of all ochratoxin A stereoisomers

The mycotoxin ochratoxin A is a potent inhibitor of the protein biosynthesis and known to be cytotoxic in nanomolar concentrations. In order to investigate the relationship between stereochemistry and cytotoxicity of this compound, all four ochratoxin A stereoisomers have been synthesized. Using the liver cell line Hep G2, the compounds were tested for cytotoxic and apoptotic potential. It could be shown, that the l-configuration of the phenylalanine moiety of the molecule is mostly responsible for the high cytotoxicity of ochratoxin A while the stereocenter at the dihydroisocoumarine structure is of less importance.     

Total synthesis and evaluation of [18F]MHMZ

Radiochemical labeling of MDL 105725 using the secondary labeling precursor 2-[(18)F]fluoroethyltosylate ([(18)F]FETos) was carried out in yields of approximately 90% synthesizing [(18)F]MHMZ in a specific activity of approximately 50MBq/nmol with a starting activity of approximately 3GBq. Overall radiochemical yield including [(18)F]FETos synthon synthesis, [(18)F]fluoroalkylation and preparing the injectable [(18)F]MHMZ solution was 42% within a synthesis time of approximately 100 min. The novel compound showed excellent specific binding to the 5-HT(2A) receptor (K(i)=9.0 nM) in vitro and promising in vivo characteristics.     

Total synthesis and evaluation of lamellarin alpha 20-Sulfate analogues

In order to explore the influence of sulfate groups on the bioactivity profiles of marine alkaloids of the lamellarin class, three such alkaloids, lamellarin alpha, lamellarin alpha 13,20-disulfate and lamellarin H, were synthesized and their activities against HIV-1 integrase and cancer cell lines were compared with those of lamellarin alpha 20-sulfate, which is a selective inhibitor of HIV-1 integrase. Lamellarin alpha does not inhibit HIV-1 integrase but shows moderate cytotoxicity with good cell line selectivity. Lamellarin alpha 13,20-disulfate is a moderate inhibitor of both HIV-1 integrase and cancer cell lines. Lamellarin H is a more potent inhibitor of HIV-1 integrase but lacked the specificity required to be medicinally useful.     

Design,synthesis and evaluation of biphenyl imidazole analogues as potent antifungal agents

To further explore the structure activity relationships (SARs) of our previously discovered antifungal lead compound (1), a series of biphenyl imidazole analogues were designed, synthesized and evaluated for their in vitro antifungal activity. Many of the synthesized compounds showed excellent activity against Candida albicans and Candida tropicalis. Among these compounds, 2-F substituted analogue 12m displayed the most remarkable in vitro activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and itraconazole. Notably, the compound 12m exhibited low inhibition profiles for various human cytochrome P450 isoforms and showed low toxicity to mammalian A549 cells and U87 cells. The SARs and binding mode established in this study will be useful for further lead optimization.     

Novel and efficient synthesis and antifungal evaluation of 2,3-functionalized cholestane and androstane derivatives

Synthetic modifications of cholesterol and other traditional steroid molecules have become a promising area for the exploration and development of novel antifungal agents, especially with respect to the development of fatty-acid esters of steroids. In addition, 2,3-functionalized steroids are also compounds with potentially interesting biological properties and proper functionalization of 2,3-steroids can lead to the development of efficient syntheses of building blocks for novel fatty-acid esters of steroids. In this Letter, we outline a novel and efficient approach to the synthesis of 2,3-functionalized cholestane and androstane derivatives and present their promising preliminary antifungal activities against a number of fungal species.     

Acyl-chlorodeoxy-glycerophosphorylcholines,Part II: Total synthesis of “cyclic lysolecithin”

Reaction of 1-fattyacyl-sn-glycero-3-phosphorylcholine with triphenylphosphine — carbon tetrachloride gave 3-fattyacyl-2-chloro-2-deoxy-sn-glycero-1-phosphorylcholine together with small amounts of other chlorodeoxy isomers. 1-Chloro-1-deoxy-2-palmitoyl-rac-glycero-3-phosphorylcholine was prepared by total synthesis from 3-chloro-2-iodopropyl palmitate. The main step in the synthesis involves the nucleophilic displacement of iodide at C-2 with dibenzyl phosphate anion, which proceeds with an acyloxy migration, leading to the key intermediate 1-chloro-1-deoxy-2-palmitoyl-rac-glycero-3-(dibenzyl phosphate). Hydrogenolysis of this phosphate triester, followed by esterification with choline acetate gave the final product. The properties of the products support an earlier conclusion that the so-called “cyclic lysolecithin” is a mixture of isomeric acyl-chloro-deoxy-glycero-phosphorylcholines in which 1-chloro-1-deoxy-2-acyl-glycero-3-phosphorylcholine is the major component.     

Total synthesis and antifungal activity of 9-methoxystrobilurin L as the originally proposed 1,4-benzodioxan structure

Total synthesis of both enantiomers of 9-methoxystrobilurin L as the originally proposed 1,4-benzodioxan structure was successfully achieved. The 1H and 13C NMR spectra of synthesized 9-methoxystrobilurin L were compared with those of a naturally-occurring sample. It was strongly indicated that naturally-occurring 9-methoxystrobilurin L has not the originally reported 1,4-benzodioxan structure but a 1,5-benzodioxepin structure, the same as previously reported 9-methoxystrobilurin K. Antifungal activities of the synthesized compounds toward several typical fungi were also examined, and they were less active than 9-methoxystrobilurin K.     

PASS-predicted design, synthesis and biological evaluation of cyclic nitrones as nootropics

Out of 400 virtually designed imidazoline N-oxides, five cyclic nitrones were selected on the basis of PASS prediction as potent nootropics and were evaluated for their biological activities in albino mice. The selected N-alkyl and aryl-substituted nitrones were found to be excellent nootropics. A series of lead compounds acting as cognition enhancers have been provided, which can be further exploited in search of such New Chemical Entities (NCEs).     

Total synthesis and biological evaluation of ustiloxin natural products and two analogs

Synthetic investigations of ustiloxin natural products are described. The first total synthesis of ustiloxin F was completed in 15 steps via ethynyl aziridine ring-opening by a phenol derivative. The results of biological tests of synthetic ustiloxins D and F, and two analogs, O-Me-ustiloxin D and 6-Ile-ustiloxin, demonstrated that the free hydroxyl group ortho to the ether linkage is critical for activity and variations at the Val/Ala site produce changes in the biological activity suggesting the need for further perturbations at this site to more extensively study the tubulin binding.     

Synthesis and antifungal activities of cyclic octa-lipopeptide burkholdine analogues

Synthesis and antifungal activity of cyclic octapeptide derivatives of burkholdines are described. To construct cyclic octapeptides, the combination of Fmoc-SPPS and cyclization with DIC/HOBt in the solution phase was employed. Synthesized peptides were evaluated for antifungal activity with MIC values against Saccharomyces cerevisiae, Aspergillus oryzae, and Candida viswanathii. As a result, the lipid side chain and the stereochemistry of each amino acid of Bk-1097 analogues significantly affected antifungal activity.     

Design,synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51

To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC–MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.     

Novel potentially antifungal hybrids of 5-flucytosine and fluconazole: Design,synthesis and bioactive evaluation

A series of novel potentially antifungal hybrids of 5-flucytosine and fluconazole were designed, synthesized and characterized by ¹H NMR, ¹³C NMR, IR and HRMS spectra. Bioactive assay manifested that some prepared compounds showed moderate to good antifungal activities in comparison with fluconazole and 5-flucytosine. Remarkably, the 3,4-dichlorobenzyl hybrid 7h could inhibit the growth of C. albicans ATCC 90023 and clinical resistant strain C. albicans with MIC values of 0.008 and 0.02?mM, respectively. The active molecule 7h could not only rapidly kill C. albicans but also efficiently permeate membrane of C. albicans. Molecular docking study revealed that compound 7h could interact with the active site of CACYP51 through hydrogen bond. Quantum chemical studies were also performed to explain the high antifungal activity. Further preliminary mechanism research suggested that molecule 7h could intercalate into calf thymus DNA to form a steady supramolecular complex, which might block DNA replication to exert the powerful bioactivities.     

Total synthesis and antifungal activity of (2S,3R)-2-aminododecan-3-ol

We report the total synthesis of (2S,3R)-2-aminododecan-3-ol has been achieved starting from commercially available 10-undecenoic acid. The key steps involved are Sharpless asymmetric epoxidation, Miyashita's boron-directed C-2 regioselective azidolysis, generated the asymmetric centers and in situ detosylation and reduction of azido tosylate. The antifungal activity of the synthesized (2S,3R)-2-aminododecan-3-ol was evaluated on several Candida strains and was comparable to miconazole, a standard drug.     

Microwave-assisted synthesis of N-substituted cyclic imides and their evaluation for anticancer and anti-inflammatory activities

A number of N-substituted cyclic imides 3a–e, 5a–e, 7a–d, and 9a–e have been synthesized in very high yields, by condensation of various diacids 2, 4, 6, and 8 with different amines under microwave irradiation. These compounds were screened for anticancer and anti-inflammatory activities, and compounds 3c, 3e, 5c, 9c, and 9d exhibited anticancer activity against colon (COLO 205) cancer better than 5-fluorouracil and mitomycin-C, and compound 9b exhibited anti-inflammatory activity better than standard drug phenyl butazone.