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Acinetobacter baumannii is a nosocomial pathogen of serious healthcare concern that is becoming increasingly difficult to treat due to antibiotic treatment failure. Recent studies have revealed that clinically defined antibiotic-susceptible strains upregulate the expression of a repertoire of putative drug efflux pumps during their growth under biologically relevant conditions, e.g., in human serum, resulting in efflux-associated resistance to physiologically achievable antibiotic levels within a patient. This phenomenon, termed Adaptive Efflux Mediated Resistance (AEMR), has been hypothesized to account for one mechanism by which antibiotic-susceptible A. baumannii fails to respond to antibiotic treatment. In the current study, we sought to identify genetic determinants that contribute to A. baumannii serum-associated AEMR by screening a transposon mutant library for members that display a loss of the AEMR phenotype. Results revealed that mutation of a putative pirin-like protein, YhaK, results in a loss of AEMR, a phenotype that could be complemented by a wild-type copy of the yhaK gene and was verified in a second strain background. Ethidium bromide efflux assays confirmed that the loss of AEMR phenotype due to pirin-like protein mutation correlated with reduced overarching efflux capacity. Further, flow cytometry and confocal microscopy measures of a fluorophore 7-(dimethylamino)-coumarin-4-acetic acid (DMACA)-tagged levofloxacin isomer, ofloxacin, further verified that YhaK mutation reduces AEMR-mediated antibiotic efflux. RNA-sequencing studies revealed that YhaK may be required for the expression of multiple efflux-associated systems, including MATE and ABC families of efflux pumps. Collectively, the data indicate that the A. baumannii YhaK pirin-like protein plays a role in modulating the organism’s adaptive efflux-mediated resistance phenotype.

Vancomycin-resistant enterococci (VRE), consisting of pathogenic Enterococcus faecalis and E. faecium, is a leading cause of hospital-acquired infections (HAIs). We recently repurposed the FDA-approved human carbonic anhydrase (CA) inhibitor acetazolamide (AZM) against VRE agent with the likely mechanism of action for the molecules being inhibition of one, or both, of the bacterial CA isoforms expressed in VRE. To elucidate how inhibitor binding to the enzymes relates to MIC, we further characterised the inhibition constants (K (i)) against the E. faecium alpha-CA (Ef alpha-CA) and gamma-CA (Ef gamma-CA), as well as against human CA I (hCAI) and human CA II (hCAII) to assess selectivity. We have also utilised homology modelling and molecular dynamics (MD) simulations to gain a better understanding of the potential interactions the molecules are making with the targets. In this paper, we elaborate on the SAR for the AZM analogs as it pertains to MIC and K (i) for each CA. Purdue Institute for Drug Discovery Programmatic; NIH/NIAID [1R01AI148523]; Italian Ministry for University and Research [FISR2019_04819] Published version The research program was partially funded by a Purdue Institute for Drug Discovery Programmatic [Grant (M.N.S and D.P.F.) and NIH/NIAID 1R01AI148523 (M.N.S and D.P.F.)]. This work was also supported by the Italian Ministry for University and Research, [grant FISR2019_04819 BacCAD (C.T.S.)].

Venezuelan and eastern equine encephalitis viruses (VEEV and EEEV, respectively) are mosquito-borne, neuroinvasive human pathogens for which no FDA-approved therapeutic exists. Besides the biothreat posed by these viruses when aerosolized, arthropod transmission presents serious health risks to humans, as demonstrated by the 2019 outbreak of EEE disease in the United States that resulted in 38 confirmed cases, 19 deaths, and neurological effects in survivors. Here, we describe the discovery of a 2-pyrrolidinoquinazolinone scaffold, efficiently synthesized in two to five steps, whose structural optimization resulted in profound antiviral activity. The lead quinazolinone, BDGR-49, potently reduced cellular VEEV and EEEV titers by >7 log at 1 μM and exhibited suitable intravenous and oral pharmacokinetic profiles in BALB/c mice to achieve excellent brain exposure. Outstanding in vivo efficacy was observed in several lethal, subcutaneous infection mouse models using an 8-day dosing regimen. Prophylactically administered BDGR-49 at 25 mg kg −1 per day fully protected against a 10× LD 50 VEEV Trinidad donkey (TrD) challenge in BALB/c mice. Similarly, we observed 70% protection when 10× LD 50 EEEV FL93-939–infected C57BL/6 mice were treated prophylactically with BDGR-49 at 50 mg kg −1 per day. Last, we observed 100% therapeutic efficacy when mice, challenged with 10× LD 50 VEEV TrD, were dosed at 48 hours after infection with BDGR-49 at 25 mg kg −1 per day. Mouse brain viral titers at 96 hours after infection were reduced to values near the limit of detection. Collectively, these results underscore the substantial development potential of a well-tolerated, brain-penetrant lead compound that shows promise in preventing and treating encephalitic alphavirus disease.

Biomimetic actuators with stimuli-responsiveness, adaptivity, and designability have attracted extensive attention. Recently, soft intelligent actuators based on stimuli-responsive materials have been gradually developed, but it is still challenging to achieve various shape manipulations of actuators through a simple 3D printing technology. In this paper, a 3D printing strategy based on magneto-active materials is developed to manufacture various biomimetic magnetic actuators, in which the new printable magnetic filament is composed of a thermoplastic rubber material and magnetic particles. The continuous shape transformation of magnetic actuators is further demonstrated to imitate the motion characteristic of creatures, including the predation behavior of octopus tentacles, the flying behavior of the butterfly, and the flower blooming behavior of the plant. Furthermore, the magnetic field-induced deformation of the biomimetic structure can be simulated by the finite element method, which can further guide the structural design of the actuators. This work proves that the biomimetic actuator based on soft magneto-active materials has the advantages of programmable integrated structure, rapid prototyping, remote noncontact actuation, and rapid magnetic response. As a result, this 3D printing method possesses broad application prospects in soft robotics and other fields.

Neisseria gonorrhoeae is an urgent threat to public health in the United States and around the world. Many of the current classes of antibiotics to treat N. gonorrhoeae infection are quickly becoming obsolete due to increased rates of resistance. Thus, there is a critical need for alternative antimicrobial targets and new chemical entities. Our team has repurposed the FDA-approved carbonic anhydrase inhibitor scaffold of acetazolamide to target N. gonorrhoeae and the bacteria's essential carbonic anhydrase, NgCA. This study established both structure-activity and structure-property relationships that contribute to both antimicrobial activity and NgCA activity. This ultimately led to molecules 20 and 23, which displayed minimum inhibitory concentration values as low as 0.25 μg/mL equating to an 8- to 16-fold improvement in antigonococcal activity compared to acetazolamide. These analogues were determined to be bacteriostatic against the pathogen and likely on-target against NgCA. Additionally, they did not exhibit any detrimental effects in cellular toxicity assays against both a human endocervical (End1/E6E7) cell line or colorectal adenocarcinoma cell line (Caco-2) at concentrations up to 128 μg/mL. Taken together, this study presents a class of antigonococcal agents with the potential to be advanced for further evaluation in N. gonorrhoeae infection models.

Vancomycin-resistant enterococci (VRE), consisting of pathogenic

Venezuelan and eastern equine encephalitis viruses are disease-causing, neuropathic pathogens with no approved treatment options in humans. While expanding the pharmacophoric model of antialphaviral amidines prepared via a quinazolinone rearrangement, we discovered that diamine-treated, 2-dihalomethylquinolinones unexpectedly afforded ring-expanded piperazine-fused benzodiazepinones. Notably, this new chemotype (19 examples) showed potent, submicromolar inhibition of virus-induced cell death,7-log reduction of viral yield, and tractable structure-activity relationships across both viruses. Antiviral activity was confirmed in primary human neuronal cells. A mechanistic rationale for product formation is proposed, and key structural elements were comparatively modeled between a similarly substituted antiviral amidine and piperazinobenzodiazepinone prototypes to guide future antiviral development.

Staphylococcus aureus is well-recognized to cause debilitating bacterial infections that are difficult to treat due to the emergence of antibiotic resistance. As such, there is a need to develop new antimicrobials for the therapeutic intervention of S. aureus disease. To that end, S. aureus RnpA is an essential enzyme that is hypothesized to participate in two required cellular processes, precursor tRNA (ptRNA) maturation and mRNA degradation. Corresponding high throughput screening campaigns have identified the phenylcarbamoyl cyclic thiopenes as a chemical class of RnpA inhibitors that display promising antibacterial effects by reducing RnpA ptRNA and mRNA degradation activities and low human cell toxicity. Herein, we perform a structure activity relationship study of the chemical scaffold. Results revealed that the cycloalkane ring size and trifluoroacetamide moiety are required for antibacterial activity, whereas modifications of the para and/or meta positions of the pharmacophore’s phenyl group allowed tuning of the scaffold’s antimicrobial performance and RnpA inhibitory activity. The top performing compounds with respect to antimicrobial activity also did not exhibit cytotoxicity to human cell lines at concentrations up to 100 µM, greater than 100-fold the minimum inhibitory concentration (MIC). Focused studies of one analog, RNP0012, which exhibited the most potent antimicrobial and inhibition of cellular RnpA activities revealed that the compound reduced bacterial burden in a murine model of S. aureus disease. Taken together, the results presented are expected to provide an early framework for optimization of next-generation of RnpA inhibitor analogues that may represent progenitors of a new class of antimicrobials.

Neisseria gonorrhoeae is an urgent threat to public health in the United States and around the world. Many of the current classes of antibiotics to treat N. gonorrhoeae infection are quickly becoming obsolete due to increased rates of resistance. Thus, there is a critical need for alternative antimicrobial targets and new chemical entities. Our team has repurposed the FDA-approved carbonic anhydrase inhibitor scaffold of acetazolamide to target N. gonorrhoeae and the bacteria’s essential carbonic anhydrase, NgCA. This study established both structure-activity and structure-property relationships that contribute to both antimicrobial activity and NgCA activity. This ultimately led to molecules 20 and 23, which displayed minimum inhibitory concentration values as low as 0.25 μg/mL equating to an 8- to 16-fold improvement in anti-gonococcal activity compared to acetazolamide. These analogs were determined to be bacteriostatic against the pathogen and likely on-target against NgCA. Additionally, they did not exhibit any detrimental effects in cellular toxicity assays against both a human endocervical (End1/E6E7) cell line or colorectal adenocarcinoma cell line (Caco-2) at concentrations up to 128 μg/mL. Taken together, this study presents a class of anti-gonococcal agents with the potential to be advanced for further evaluation in N. gonorrhoeae infection models.

Staphylococcus aureus is well-recognized to cause debilitating bacterial infections that are difficult to treat due to the emergence of antibiotic resistance. As such, there is a need to develop new antimicrobials for the therapeutic intervention of S. aureus disease. To that end, S. aureus RnpA is an essential enzyme that is hypothesized to participate in two required cellular processes, precursor tRNA (ptRNA) maturation and mRNA degradation. Corresponding high throughput screening campaigns have identified the phenylcarbamoyl cyclic thiopenes as a chemical class of RnpA inhibitors that display promising antibacterial effects by reducing RnpA ptRNA and mRNA degradation activities and low human cell toxicity. Herein, we perform a structure activity relationship study of the chemical scaffold. Results revealed that the cycloalkane ring size and trifluoroacetamide moiety are required for antibacterial activity, whereas modifications of the para and/or meta positions of the pharmacophore’s phenyl group allowed tuning of the scaffold’s antimicrobial performance and RnpA inhibitory activity. The top performing compounds with respect to antimicrobial activity also did not exhibit cytotoxicity to human cell lines at concentrations up to 100 µM, greater than 100-fold the minimum inhibitory concentration (MIC). Focused studies of one analog, RNP0012, which exhibited the most potent antimicrobial and inhibition of cellular RnpA activities revealed that the compound reduced bacterial burden in a murine model of S. aureus disease. Taken together, the results presented are expected to provide an early framework for optimization of next-generation of RnpA inhibitor analogues that may represent progenitors of a new class of antimicrobials.

A novel membrane sound absorber based on the magnetorheological membrane (MRM) is developed for active sound absorption. Due to its good flexibility and stretch-ability, the MRM consisting of carbonyl iron particles (CIPs) and polydimethylsiloxane (PDMS) elastomer matrix can be easily deformed. The deformation of MRM is investigated by the digital image correlation method. The off-plane displacement is positively related to both of the CIPs mass fractions and magnetic field strength. The sound absorption performance of MRM sound absorber is investigated and it is found that the thickness of the membrane, CIPs mass fractions, and air cavity length behind the membrane significantly influence the sound absorption performance. The magnetic field can adjust the sound absorption frequency without affecting the high acoustical absorption coefficients. The double-layer membrane structure has two sound absorption peaks within the testing frequency range and further improves the frequency adjustability of the sound absorber. Therefore, it is expected to be a particularly promising alternative for active sound absorption. Finally, the numerical solutions calculated by the equivalent circuit method also support the experimental results.

Vancomycin-resistant enterococci (VRE) are the second leading cause of hospital-acquired infections (HAIs) attributed to a drug-resistant bacterium in the United States and resistance to the frontline treatments is well documented. To combat VRE, we have repurposed the FDA-approved carbonic anhydrase drug acetazolamide to design potent anti-enterococcal agents. Through structure-activity relationship optimization we have arrived at two leads possessing improved potency against clinical VRE strains from MIC = 2 μg/mL (acetazolamide) to MIC = 0.007 μg/mL (22) and 1 μg/mL (26). Physicochemical properties were modified to design leads that either have high oral bioavailability to treat systemic infections or low intestinal permeability to treat VRE infections in the gastrointestinal tract. Our data suggests the intracellular target for the molecules are putative α-carbonic and γ-carbonic anhydrases and homology modeling and molecular dynamics simulations were performed. Together, this study presents potential anti-VRE therapeutic options to provide alternatives for problematic VRE infections.

Acinetobacter baumannii is a nosocomial pathogen of urgent concern for public health due to rising rates of multidrug and pandrug resistance. In the context of environmental cues such as growth in human serum, A. baumannii is known to display adaptive efflux, in which a multitude of efflux-associated genes are upregulated, resulting in efflux-mediated drug tolerance in strains that are otherwise susceptible to antibiotic therapy. Previously, we identified a sulfonamide-containing scaffold molecule (ABEPI1) that reversed serum-associated antibiotic tolerance in A. baumannii. Herein, we present structure-activity relationship studies on 29 newly synthesized analogues. These molecules were characterized for their ability to potentiate multiple antibiotics in serum, reduce serum-associated ethidium bromide efflux and depolarize bacterial cell membranes. In addition, they were assessed for toxicity to mammalian cells. Collectively, these molecules may represent promising potential adjuvants for use in combination with new and existing antibiotics to treat A. baumannii bacterial infections.

Acoustic structures with active control capabilities are crucial in practical noise reduction. In this work, magnetic tunable sound absorption channels were developed to achieve magnetic acoustic control. The magnetic switch made of hard magnetic composites were inserted in the channel and their magnetic anisotropy was utilized to shift the frequency of peak sound absorption. The sound absorption channels were composed of several lateral Helmholtz units with different lengths, which possessed tunable sound absorption peaks by varying the volume of the channels. The peak sound absorption frequency was inversely proportional to the length of the Helmholtz units and multiple units with similar lengths could produce continuous sound absorption peaks in one sound absorption channel. Owing to the magnetic anisotropy, the magnetic switches performed different force and movement statuses under magnetic fields with different directions. The surface treated magnetic switches could slide in the channels smoothly by magnetic fields with different directions, which could turn the sound absorption channels in the whole testing frequency range. Therefore, the magnetic sound absorption channels exhibit excellent tunability under applying the external magnetic fields and promise a great potential in complex magnetic control.

Owing to the flexible and controllable characteristics, the magnetic composite film becomes an ideal option for future portable, efficient and multifunctional magnetic soft actuators. Here, an anisotropic magneto-sensitive elastomer film (MSEF) composite based on polydimethylsiloxane (PDMS) and high concentration of carbonyl iron particles (CIPs) was developed. The off-plane design of CIP structures endows MSEF excellent field-dependent deformability and actuation ability. The off-plane bending angle of the MSEF-30° in 87mT uniform magnetic field could reach 70.78°. Moreover, the MSEF-20° could lift a heavy object 66.4 times its own weight. The influences of particle chain orientation, CIP contents, thickness and applied magnetic field on the magneto-induced deformation behavior were fully discussed, and finite element calculations were performed to clarify the experimental results. An improved balance equation was proposed and qualitatively explained the experimental results under different magnetic fields. Based on the MSEF composite, biomimetic soft actuators with bidirectional deformation and self-sensing functions were produced respectively. The two easy preparation and programmable soft actuators could achieve the expected actuation effect, indicating that the anisotropic MSEFs have great potential as soft actuators in the fields of biomedicine, microfluidics, intelligent robots and bionics applications.

An improved laboratory synthesis of YC-071, a potent azole antifungal agent, has been developed. Compared with the original route, the new route is operationally simple, requiring only limited purification of all the intermediates. The new route is an important scalable synthesis, which meets the need for YC-071 for use in preclinical studies.

An efficient four-step, six-transformation protocol was developed to afford bioactive N-alkyl- or N-arylamide (E)-arylamidines featuring strategic amidine C3 modifications which were inaccessible or low yielding by previous methods. This synthetic approach, exemplified with 24 amidines and requiring only a single purification, highlights a multicomponent Ugi–Mumm rearrangement to afford highly diversified quinazolinones which undergo regiospecific rearrangement to afford new amidines. The method extensively broadens the structural scope of this new class of trisubstituted amidines and demonstrates the tolerance of regional C3 amidine steric bulk, visualized with X-ray crystallographic analysis.

Leucine-rich repeat receptor-like kinase protein (LRR-RLK) is involved in a wide range of biological pathways. So far, the function of LRR-RLK in the growth, developmental processes and various external stimuli has still not been clearly elucidated in rice (Oryza sativa L.). To understand the mechanism(s) underlying stress response and to discover novel stress-tolerance genes in rice, we analysed a global genome expression profiling of the indica cultivar Pei'ai 64S subjected to cold, drought or heat stresses. Expression profiles were obtained for leaf and panicle tissues at seedling, booting and heading stages from plants under no stress, or cold, drought or heat stress, using the GeneChip Rice Genome Array (Affymetrix) representing 51279 transcripts from japonica and indica rice. We identified a gene, OsLRR2 (Oryza sativa L. leucine-rich repeat receptor-like kinase 2, GenBank accession: EAZ02952.1), which was highly up-regulated under cold and drought stress. In order to study its function in stress tolerance, we cloned the cDNA of the gene through amplification by reverse-transcription polymerase chain reaction. Sequence analysis showed that the cDNA encodes a protein of 375 amino-acid residues with molecular weight of ≈40.62 kD and pI of ≈5.75. The sequence databases search found that the open reading frame of OsLRR2 contained a leucine-rich repeats domain. Analysis of the putative promoter region for candidate cis-regulatory elements identified five matches to cis-elements related to stress responses, suggesting that OsLRR2 could be considered a new candidate gene involved in stress tolerance in rice.

Sulphotransferase (SOT) catalyses the transfer of a sulphonate group from 3′-phosphoadenosine 5′-phosphosulphate (PAPS) to an appropriate hydroxyl group of various substrates with the parallel formation of 3′-phosphoadenosine 5′-phosphate (PAP). Although several SOTs have been identified and characterized in mammalian, their role in plant is still unclear. In this study, we report genome-wide comprehensive expression analysis of 35 putative SOT genes in rice. The 35 OsSOTs were tandemly arranged into six clusters. The phylogenetic analysis showed that there were 7 subfamilies of OsSOTs and 11 putatively conserved motifs. Six OsSOTs might be pseudogenes, 25 have the two motifs which were involved in PAPS binding regions I and IV. Microarray data indicated that all the OsSOTs were expressed almost at the same level but with different patterns: most OsSOTs were expressed exclusively in stigma and ovary and induced by IAA and BAP, several genes were induced by tZ and DMSO and 11 OsSOTs were response to abiotic stress. Further analysis showed that these 11 genes contained cis-regulatory elements responding to abiotic stresses.

A series of novel triazole derivatives containing γ-lactam were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR and HRMS. The in vitro antifungal activities of the target compounds were evaluated. The results showed that all of the compounds exhibited stronger activity against the six clinically important fungi tested than fluconazole. 3D and 3E showed comparative activity against the fungi tested except for Candida glabrata and Aspergillus fumigatus as voriconazole. In addition, the docking model for 2A and CYP51 was investigated.

Abiotic stresses may seriously affect plant growth and development. In order to explore new stress tolerance genes in rice (Oryza sativa L.), expression profiles were obtained for leaf and panicle tissues. They were taken at seedling, booting, heading and flowering stages of indica cultivar Pei'ai 64S plants under cold, drought and heat stresses by using the GeneChip Rice Genome Array (Affymetrix), which includes 51,279 transcripts from japonica and indica rice. O. sativa L. cytosolic sulphotransferase-like gene (OsSOT9) was highly induced in leafs and panicles during different developmental stages, in response to all stresses, especially at booting stage under cold stress. The quantitative real-time polymerase chain reaction analysis showed that this result was almost consensus with GeneChip Rice Genome Array. cDNA of OsSOT9 was cloned to study its function in stress tolerance through reverse transcription PCR. Sequence analysis showed that the cDNA encoded a protein with molecular weight of about 37.78 kDa and pl of about 6.6, which was composed of 343 amino acid residues. Bioinformatics data showed that the protein contained a conservative domain of the sulphotransferase (SOT) family gene. OsSOT9 was found to be closely related to the cytosolic sulphotransferase after comparison of the protein sequences. Analysis of the putative promoter region found 12 kinds of cis-elements related to stress response. On the basis of the above analyses, we suggested that OsSOT9 is a novel candidate gene involved in stress tolerance in rice.

This Letter reports a magneto-active pulse pump (MAPP) consisting of a flexible check valve and a magneto-active pipe developed by using a 3D printing-assistant method. The deformation behavior of the magneto-active pipe is investigated by using the three-dimensional reconstruction, simulation, and theoretical analysis. The larger deformation under a high magnetic field produces higher driving pressure, and thus, the MAPP can be used to transfer liquid. It is found that the MAPP responds to the strength and frequency of the magnetic field simultaneously and the pumping performance can be analyzed by a magneto-fluid-solid coupling simulation. This work provides guidance for the design and manufacture of pulse pumps in future heart pump components.

Environmental hazardous stimuli including strong electromagnetic field and impact force were always harmful to human beings. Developing functional triboelectric nanogenerator (TENG) with universally harvesting various energy and anti-impact effect may be an effective strategy to collect energy as well as protect human beings from danger. Thus, a miniaturized all-in-one TENG with high structural durability, anti-impact and multi-mode harvesting energy from compression, swaying and magnetic field was developed by assembling shear thickening fluid (STF) and magneto-sensitive films. TENG yielded maximum power density of 27.05 mW/m2 with the voltage of 10.40 V at 10 MΩ under compression. It also sensed and collected tiny STF flowing energy under non-contact mode. Besides, high magnetic-sensitive effect endowed TENG with magnetic dependent programmable shapes which enabled it to harvest non-contact rubbing/deformation energy. More importantly, the device with STF exhibited high anti-impact properties which could resist and dissipate harsh collision force from 1390 N to 409 N, demonstrating excellent safeguarding properties for TENG and human wearers. This versatile device also showed reliable sensing properties to various external magnetic field, human motions, contacted materials and impact forces. In addition, a wearable TENG-based smart glove as a self-powered functional sensor presented the ability of precisely mapping finger joints. Finally, newly-designed Kevlar/TENG-based e-textile arrays with 95% impact-force dissipating and multi-fields display performance was proposed. Thus, this work opened a new perspective for the development of functional TENGs as wearable electronic devices in universally energy-scavenging and safeguarding areas.

Currently, there are no licensed human vaccines or antivirals for treatment of or prevention from infection with encephalitic alphaviruses. Because epidemics are sporadic and unpredictable, and endemic disease is common but rarely diagnosed, it is difficult to identify all populations requiring vaccination; thus, an effective post-exposure treatment method is needed to interrupt ongoing outbreaks. To address this public health need, we have continued development of ML336 to deliver a molecule with prophylactic and therapeutic potential that could be relevant for use in natural epidemics or deliberate release scenario for Venezuelan equine encephalitis virus (VEEV). We report findings from in vitro assessments of four analogs of ML336, and in vivo screening of three of these new derivatives, BDGR-4, BDGR-69 and BDGR-70. The optimal dosing for maximal protection was observed at 12.5 mg/kg/day, twice daily for 8 days. BDGR-4 was tested further for prophylactic and therapeutic efficacy in mice challenged with VEEV Trinidad Donkey (TrD). Mice challenged with VEEV TrD showed 100% and 90% protection from lethal disease when treated at 24 and 48 h post-infection, respectively. We also measured 90% protection for BDGR-4 in mice challenged with Eastern equine encephalitis virus. In additional assessments of BDGR-4 in mice alone, we observed no appreciable toxicity as evaluated by clinical chemistry indicators up to a dose of 25 mg/kg/day over 4 days. In these same mice, we observed no induction of interferon. Lastly, the resistance of VEEV to BDGR-4 was evaluated by next-generation sequencing which revealed specific mutations in nsP4, the viral polymerase.

A novel resonance sound absorber, whose resonant frequency characteristic can be varied by turning the external magnetic field, is constructed based on micro-perforated magnetorheological elastomer (MP-MRE). The influence of parameters, such as porosity, thickness, curing agent weight ratio and magnetic field intensity, are investigated to analyze the magneto-acoustic coupling property of MP-MRE sound absorber. By increasing the magnetic flux density, the resonant frequency of resonance sound absorber moves toward high frequency region. It is found the magnetic field-induced deformation of the MP-MRE and its pores affected the resonant frequency. When the magnetic flux density was increased from 0 to 132 mT, the maximum variation of the resonant frequency reached 304 Hz. Finally, originated from this unique magnetic controllability, the MP-MRE sound absorber shows broad potential in the tunable sound absorber at middle and low frequency range.

To improve the aqueous solubility of an itraconazole analogue, compound 1 (YL-24), a series of novel prodrugs were synthesized. Among these prodrugs, the phosphate disodium salt compound 7 exhibited excellent aqueous solubility (9.8 mg/mL) at near-neutral pH and sufficient stability in buffer solutions, along with favorable pharmacokinetic profiles. In particular, compounds 1 and 7 provided moderate survival efficacy in murine systemic Candida albican s SC5314 infection model, but their efficacy was weaker than that of fluconazole.

In order to find novel antifungal agents with good activity and aqueous solubility, a series of SYN-2869 analogues containing a pyridine ring were synthesized and evaluated for their in vitro antifungal activity and water solubility. The results indicated that some compounds showed potent activity against six pathogenic fungi. In particular, the analogue 17a having an isobutyl substitution on the triazolone exhibited significant broad spectrum antifungal activity. In addition, the water solubility of compound 17a was sufficiently improved over SYN-2869.

In order to further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (I), two series of novel azoles featuring thieno[2,3-c]pyrrolidone and thieno[3,2-c]pyrrolidone nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SARs of antifungal triazoles. Most of target compounds exhibited excellent activity against Candida and Cryptococcus spp., with MIC values in the range of 0.0625 μg/ml to 0.0156 μg/ml. The thieno[3,2-c]pyrrolidone unit was more suited for improving activity against Aspergillus spp. The most potent compound, 18a, was selected for further development due to its significant in vitro activity against Aspergillus spp. (MIC = 0.25 μg/ml), as well as its high metabolic stability in human liver microsomes.

Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine and tetrahydro-thiazolo[5,4-c]pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles.

Replacement of the phenyl ring in the itraconazole side chain with pyridine as a bioisostere yields a new class of antifungal agents.

To improve antifungal activities, water solubility and bioavailability, a series of novel analogues of itraconazole-containing pyridine rings were designed and synthesized. Their antifungal activities were evaluated in vitro against six clinically important fungi by measuring the minimal inhibitory concentrations (MICs). Most of the compounds showed more potent antifungal activities than that of itraconazole. In particular, the analogues 30d, 30c, 31c, and 36d exhibited much higher solubility and bioavailability than that of itraconazole. The bioavailability of 36d (42.2%) was five times higher than that of itraconazole (8%) and was negative for genetic toxicology in the Ames test.