Synthesis and antifungal evaluation of novel triazole derivatives bearing a pyrazole-methoxyl moiety.

Life-threatening invasive fungal infections pose a serious threat to human health. A series of novel triazole derivatives bearing a pyrazole-methoxyl moiety were designed and synthesized in an effort to obtain antifungals with potent, broad-spectrum activity that are less susceptible to resistance. Most of these compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and 10,231, Cryptococcus neoformans 32,609, Candida glabrata 537 and Candida parapsilosis 22,019 with minimum inhibitory concentration (MIC) values of ≤0.

The vacuolar fusion regulated by HOPS complex promotes hyphal initiation and penetration in Candida albicans.

The transition between yeast and hyphae is crucial for regulating the commensalism and pathogenicity in Candida albicans. The mechanisms that affect the invasion of hyphae in solid media, whose deficiency is more related to the pathogenicity of C. albicans, have not been elucidated.

Discovery of a Novel Potent Tetrazole Antifungal Candidate with High Selectivity and Broad Spectrum.

Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent antifungal activities against seven pathogenic fungi. Among them, tetrazole compound was the most potent antifungal with MIC values of <0.

From Synergy to Monotherapy: Discovery of Novel 2,4,6-Trisubstituted Triazine Hydrazone Derivatives with Potent Antifungal Potency and .

Invasive fungal infections pose a serious threat to public health and are associated with high mortality and incidence rates. The development of novel antifungal agents is urgently needed. Based on hit-to-lead optimization, a series of 2,4,6-trisubstituted triazine hydrazone compounds were designed, synthesized, and biological evaluation was performed, leading to the identification of compound with excellent synergy (FICI range: 0.

Late consolidation of rRNA structure during co-transcriptional assembly in by time-resolved DMS footprinting.

The production of new ribosomes requires proper folding of the rRNA and the addition of more than 50 ribosomal proteins. The structures of some assembly intermediates have been determined by cryo-electron microscopy, yet these structures do not provide information on the folding dynamics of the rRNA. To visualize the changes in rRNA structure during ribosome assembly in cells, transcripts were pulse-labeled with 4-thiouridine and the structure of newly made rRNA probed at various times by dimethyl sulfate modification and mutational profiling sequencing (4U-DMS-MaPseq).

Design, synthesis and evaluation of novel deferasirox derivatives with high antifungal potency in vitro and in vivo.

Here we designed and synthesized 58 deferasirox derivatives with the aim of discovering novel antifungal agents. Most compounds exhibited moderate to excellent in vitro antifungal activities against Cryptococcus neoformans H99 with MIC values ranging from 0.25 μg/mL to 16 μg/mL, including ten compounds with MIC values less than 1 μg/mL that were further screened against an additional six pathogenic fungi.

Design, synthesis and biological studies of novel triazoles with potent and broad-spectrum antifungal activity.

A series of novel triazole derivatives containing aryl-propanamide side chains was designed and synthesised. antifungal activity studies demonstrated that most of the compounds inhibited the growth of six human pathogenic fungi. In particular, parts of phenyl-propionamide-containing compounds had excellent, broad-spectrum antifungal activity against SC5314, 22-21, 537 and 22-20 with MIC values in the range of ≤0.

Novel antifungal triazoles with alkynyl-methoxyl side chains: Design, synthesis, and biological activity evaluation.

Previous work led to the rational design, synthesis and testing of novel antifungal triazole analogues bearing alkynyl-methoxyl side chains. Tests of in vitro antifungal activity showed Candida albicans SC5314 and Candida glabrata 537 gave MIC values of ≤0.125 μg/mL for most of the compounds.

Discovery of novel triazoles containing benzyloxy phenyl isoxazole side chain with potent and broad-spectrum antifungal activity.

As a continuation study, 29 novel triazoles containing benzyloxy phenyl isoxazole side chain were designed and synthesized based on our previous work. The majority of the compounds exhibited high potency in vitro antifungal activities against eight pathogenic fungi. The most active compounds 13, 20 and 27 displayed outstanding antifungal activity with MIC values ranging from <0.

Design, Synthesis and Structure-Activity Relationship Studies of Nicotinamide Derivatives as Potent Antifungal Agents by Disrupting Cell Wall.

Fungal infections pose a serious challenge to human health due to the limited paucity of antifungal treatments. Starting as a hit compound screened from our compound library, a series of nicotinamide derivatives have been successfully synthesized via a facile one-step coupling reaction of aromatic carboxylic acid and amine. The synthesized compounds were evaluated for their antifungal activity against SC5314.

Discovery of Novel Orally Bioavailable Triazoles with Potent and Broad-Spectrum Antifungal Activity In Vitro and In Vivo.

In our continuing efforts to discover novel triazoles with improved antifungal activity in vitro and in vivo, a series of 41 novel compounds containing 1,2,3-triazole side chains were designed and synthesized via a click reaction based on our previous work. Most of the compounds showed moderate to excellent broad-spectrum antifungal activity in vitro. Among them, the most promising compound displayed excellent antifungal and anti-drug-resistant fungal ability (MIC = 0.

Design, synthesis, and evaluation of novel tetrazoles featuring isoxazole moiety as highly selective antifungal agents.

In an effort to develop novel azole antifungals with potent activity and high selectivity, a series of (2R,3R)-3-((3-substitutied-phenyl-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)butan-2-ol derivatives were designed and synthesized based on our previously work. All compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and Cryptococcus neoformans H99, but inactive against Aspergillus fumigatus 7544. Among them, the most active compound 10h displayed outstanding antifungal activity against fluconazole-resistant C.

Discovery of Novel Thiosemicarbazides Containing 1,3,5-Triazines Derivatives as Potential Synergists against Fluconazole-Resistant .

The clinical prevalence of antifungal drug resistance has been increasing over recent years, resulting in the failure of treatments. In an attempt to overcome this critical problem, we sought novel synergistic enhancers to restore the effectiveness of fluconazole against resistant . Based on the structural optimization of hit compound from our in-house library, a series of novel 1,3,5-triazines derivatives was designed, synthesized, and biologically evaluated for synergistic activity in combination with fluconazole.

Design, synthesis, and in vitro evaluation of novel antifungal triazoles containing substituted 1,2,3-triazole-methoxyl side chains.

In order to develop new triazole derivatives, we optimized the lead compound a6 by structural modifications to obtain a series of (2R,3R)-3-((1-substituted-1H-1,2,3-triazol-4-yl) methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, compounds 5-36. Most of the target compounds exhibited excellent in vitro antifungal activity against Candida albicans 10231 and Candida glabrata 537 with MIC ≤ 0.125 µg/mL.

Discovery of Novel 7-Hydroxy-5-oxo-4,5-dihydrothieno[3,2-]pyridine-6-carboxamide Derivatives with Potent and Selective Antifungal Activity against Species.

and can cause fatal invasive infections, especially in immunocompromised patients. However, few antifungal drugs are available to help treat cryptococcosis. In this study, by compound library screening, we presented the first report of hit compound , which had potent and antifungal activity against spp.

Design, Synthesis, and In Vitro and In Vivo Antifungal Activity of Novel Triazoles Containing Phenylethynyl Pyrazole Side Chains.

A series of triazole derivatives containing phenylethynyl pyrazole moiety as side chain were designed, synthesized, and most of them exhibited good in vitro antifungal activities. Especially, compounds and showed excellent in vitro activities against (MIC = 0.125, 0.

Design, synthesis, and in vitro evaluation of novel triazole analogues featuring isoxazole moieties as antifungal agents.

In order to develop novel antifungal agents, based on our previous work, a series of (2R,3R)-3-((3-substitutied-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (a1-a26) were designed and synthesized. All of the compounds exhibited good in vitro antifungal activities against eight human pathogenic fungi. Among them, compound a6 showed excellent inhibitory activity against Candida albicans and Candida parasilosis with MIC values of 0.

Design, synthesis, and structure-activity relationship studies of novel triazole agents with strong antifungal activity against Aspergillus fumigatus.

The incidence of invasive fungal infections has dramatically increased for several decades. In order to discover novel antifungal agents with broad spectrum and anti-Aspergillus efficacy, a series of novel triazole derivatives containing 1,2,3-benzotriazin-4-one was designed and synthesized. Most of the compounds exhibited stronger in vitro antifungal activities against tested fungi than fluconazole.

A newborn RNA switches its fate.

Riboswitches enable microbes to rapidly respond to changing levels of metabolites. A high-throughput platform reveals how RNA structural transitions kinetically compete during transcription in a new mechanism for riboswitch function.

Role of Era in assembly and homeostasis of the ribosomal small subunit.

Assembly factors provide speed and directionality to the maturation process of the 30S subunit in bacteria. To gain a more precise understanding of how these proteins mediate 30S maturation, it is important to expand on studies of 30S assembly intermediates purified from bacterial strains lacking particular maturation factors. To reveal the role of the essential protein Era in the assembly of the 30S ribosomal subunit, we analyzed assembly intermediates that accumulated in Era-depleted Escherichia coli cells using quantitative mass spectrometry, high resolution cryo-electron microscopy and in-cell footprinting.

Time-Resolved Hydroxyl Radical Footprinting of RNA with X-Rays.

RNA footprinting by hydroxyl radical cleavage provides 'snapshots' of RNA tertiary structure or protein interactions that bury the RNA backbone. Generation of hydroxyl radicals with a high-flux synchrotron X-ray beam provides analysis on a short timescale (5-100 msec), which enables the structures of folding intermediates or other transient conformational states to be determined in biochemical solutions or cells. This article provides protocols for using synchrotron beamlines for hydroxyl radical footprinting.

Design, synthesis, and SAR study of 3-(benzo[d][1,3]dioxol-5-yl)-N-benzylpropanamide as novel potent synergists against fluconazole-resistant Candida albicans.

Based on our previous discovery and SAR study on the lead compounds 7d, 5 and berberine which can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, a series of 3-(benzo[d][1,3]dioxol-5-yl)-N-(substituted benzyl)propanamides were designed, synthesized, and evaluated for their in vitro synergistic activity in combination with fluconazole. The series 2a-f were designed by replacing the amide moiety of the lead compound 7d with retro-amide moiety, and compounds 2a and 2b showed more activity than the lead 7d. Furthermore, introducing biphenyl moiety into series 2d-f afforded series 3a-r, most of which exhibited significantly superior activity to the series 2d-f.

Three-way junction conformation dictates self-association of phage packaging RNAs.

The packaging RNA (pRNA) found in the phi29 family of bacteriophage is an essential component of a powerful molecular motor used to package the phage's DNA genome into the capsid. The pRNA forms homomultimers mediated by intermolecular "kissing-loop" interactions, thus it is an example of the unusual phenomenon of a self-associating RNA that can form symmetric higher-order multimers. Previous research showed the pRNAs from phi29 family phages have diverse self-association properties and the kissing-loop interaction is not the sole structural element dictating multimerization.