Invasive candidiasis, particularly those caused by drug-resistant Candida albicans, poses a serious threat worldwide. To develop novel antifungal agents, a series of triazine thiosemicarbazide derivatives were designed and synthesized via structure optimization. Structure-activity relationship analysis revealed that the thiosemicarbazide moiety is essential for synergistic antifungal activity. Notably, compound A21 exhibited excellent synergistic effects with fluconazole (FCZ) against resistant C. albicans (lowest FICI range: 0.002-0.005), restoring the efficacy of other azoles and showing monotherapy activity against Candida glabrata (MIC = 1 μg/mL) and Cryptococcus neoformans (MIC = 4 μg/mL). Mechanistically, A21 reversed FCZ resistance by downregulating ERG genes, as well as drug resistance- and virulence-related genes, when combined with FCZ. With enhanced metabolic stability in human liver microsomes (HLM) and mouse liver microsomes (MLM) and a favorable safety profile, A21 in combination with FCZ displayed potent in vivo efficacy against Galleria mellonella and mice infected with resistant C. albicans. Therefore, A21 represents a promising lead for combating resistant candidiasis.

The growing incidence and prevalence of invasive fungal infections (IFIs) and the emergence of antimicrobial resistance compound clinical antifungal therapies. Given the significant threat posed by IFIs and the limits of the current antifungal agents, the search for novel, effective therapeutic options remains a compelling area of antifungal drug discovery. The s-triazine (1,3,5-triazine) scaffold, renowned for its structural versatility, ease of functionalization, and diverse biological profiles, has been extensively studied in medical chemistry. Driven by this privileged structure, several s-triazine derivatives have been synthesized through molecular hybridization and screened for their antifungal activities. Some of them demonstrated potent efficacy against pathogenic fungi, including Candida, Cryptococcus, and Aspergillus species. Structure–activity relationship (SAR) studies are also discussed whenever possible, underlying the essential substituents for their antifungal effect. This review provides a summary of recent advancements (2014–2024) in the development of antifungal agents featuring the s-triazine scaffold and highlights the antifungal activity of s-triazine derivatives, aiming to prompt further progress in this field.

Due to clinical demands, there remains a need for new triazole antifungal compounds to broaden the antifungal spectrum and enhance therapeutic efficacy. In this paper, we have developed an effective method for obtaining triazole compounds with 1,2,3-triazole groups introduced into their side chains via click chemistry, targeting the active site of cytochrome P450 14 alpha-demethylase (CYP51). In vitro antifungal activity tests of the title compounds against three human pathogenic fungi demonstrated that this class of compounds exhibited good antifungal activity. Notably, compound 2d exhibits superior antifungal activity compared to fluconazole against Candida albicans SC5314 (with the MIC value of <= 0.125 mu g/mL) and Cryptococcus neoformans 32609 (with the MIC value of 2 mu g/mL), meriting further investigation. Molecular docking results indicated that the introduced 1,2,3-triazole rings in the side chains formed pi-pi stacking interactions with Tyr118 of CYP51, along with additional hydrogen bonds. This paper provides a method for rapidly modifying the side chains of triazole antifungal drugs in the future to obtain compounds with further enhanced activity.

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 ≤0.125 μg/mL to 0.5 μg/mL. Use of recombinant Saccharomyces cerevisiae strains showed compounds 7 and 10 overcame the overexpression and resistant-related mutations in ERG11 of S. cerevisae and several pathogenic Candida spp. Despite being substrates of the C. albicans and Candida auris Cdr1 drug efflux pumps, compounds 7 and 10 showed moderate potency against five fluconazole (FCZ)-resistant fungi with MIC values from 2.0 μg/mL to 16.0 μg/mL. Growth kinetics confirmed compounds 7 and 10 had much stronger fungistatic activity than FCZ. For C. albicans, compounds 7 and 10 inhibited the yeast-to-hyphae transition, biofilm formation and destroyed mature biofilm more effectively than FCZ. Preliminary mechanism of action studies showed compounds 7 and 10 blocked the ergosterol biosynthesis pathway at Erg11, ultimately leading to cell membrane disruption. Further investigation of these novel triazole derivatives is also warranted by their predicted ADMET properties and low cytotoxicity.

Invasive fungal infections (IFIs) pose a serious threat to human health and are associated with high morbidity and mortality. In addition, the emergence of drug-resistant fungi has created an unmet medical need for the development of new classes of antifungal agents. The s-triazines are six-membered, nitrogen-containing heterocyclic scaffolds with a broad range of biological properties and have received considerable attention in medical chemistry. This review highlights recent literature reports of s-triazines derivatives as potential antifungal agents with a focus on their structure-activity relationships (SAR) which paves the way for the design and synthesis of more active s-triazine antifungal candidates.

Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent in vitro antifungal activities against seven pathogenic fungi. Among them, tetrazole compound D2 was the most potent antifungal with MIC values of <0.008, <0.008, and 2 mu g/mL against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus, respectively, the three most common and critical priority pathogenic fungi. In addition, compound D2 also exhibited potent activity against fluconazole-resistant C. auris isolates. Notably, compound D2 showed a lower inhibitory activity in vitro against human CYP450 enzymes as well as a lower inhibitory effect on the hERG K+ channel, indicating a low risk of drug-drug interactions and QT prolongation. Moreover, with improved pharmacokinetic profiles, compound D2 showed better in vivo efficacy than albaconazole at reducing fungal burden and extending the survival of C. albicans-infected mice. Taken together, compound D2 will be further investigated as a promising candidate.

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 28 with excellent in vitro synergy (FICI range: 0.094-0.38) and improved monotherapy potency against fluconazole-resistant Candida albicans and Candida auris (MIC range: 1.0-16.0 mu g/mL). Moreover, 28 exhibited broad-spectrum antifungal activity against multiple pathogenic strains. Furthermore, 28 could inhibit hyphal and biofilm formation, which may be related to its ability to disrupt the fungal cell wall. Additionally, 28 significantly reduced the CFU in a mouse model of disseminated infection with candidiasis at a dose of 10 mg/kg. Overall, the triazine-based hydrazone compound 28 with low cytotoxicity, hemolysis, and favorable ADME/T characteristics represents a promising lead to further investigation.

AbstractThe transition between yeast and hyphae is crucial for regulating the commensalism and pathogenicity inCandida albicans. The mechanisms that affect the invasion of hyphae in solid media, whose deficiency is more related to the pathogenicity ofC. albicans, have not been elucidated. Here, we found that the disruption ofVAM6orVPS41which are components of the homotypic vacuolar fusion and protein sorting (HOPS) complex, or the Rab GTPaseYPT72, all responsible for vacuole fusion, led to defects in hyphal growth in both liquid and solid media, but more pronounced on solid agar. The phenotypes ofvac8Δ/Δ andGTR1OE-vam6Δ/Δ mutants indicated that these deficiencies are mainly caused by the reduced mechanical forces that drive agar and organs penetration, and confirmed that large vacuoles are required for hyphal mechanical penetration. In summary, our study revealed that large vacuoles generated by vacuolar fusion support hyphal penetration and provided a perspective to refocus attention on the role of solid agar in evaluatingC. albicansinvasion.

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. This class of compounds showed high potency against Candida glabrata with MIC values ranging from <0.125 μg/mL to 1 μg/mL. We identified that compound 54 has high potency against 14 strains of Candida glabrata spp. and Cryptococcus spp. with MIC values ranging from <0.125 μg/mL to 1 μg/mL. In addition, compound 54 significantly reduced the CFU in a mouse model of disseminated infection with Cryptococcus neoformans H99 at a dose of 10 mg/kg, which is comparable to FLC. Further investigations on compound 54 are currently in progress.

Organic chemistry is a fundamental course for undergraduate students majoring in clinical disciplines at our university,playing a crucial"bridge"role in their subsequent professional courses.However,organic chemistry is known for its abstract theoretical concepts and numerous knowledge points,making it challenging for students to comprehend and master.In response to the teaching issues encountered in traditional classroom settings,this paper adopts the innovative O-PIRTAS flipped classroom model,integrating the characteristics of organic chemistry education.Taking the specific topic of carboxylic acids as an example,the classroom teaching is restructured with the aim of exploring the application of this model in organic chemistry courses and subsequently improving teaching effectiveness.

BOPPPS教学模式是一种逻辑清晰、教学节奏紧凑的教学模型,按照模块设置顺序,包含了导入、目标、前测、参与式学习、后测和总结六大部分.针对临床专业有机化学课时数少、知识点零碎、理论抽象等特点,教学团队运用BOPPPS教学模式,以"羧酸"章节授课为例,探讨该模式在有机化学课程中的应用.

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. Among these, compounds 16, 18, and 29 displayed broad-spectrum antifungal activity against seven human pathogenic fungal species, two fluconazole-resistant C. albicans isolates and two multi-drug resistant Candida auris isolates. Moreover, 0.5 μg/mL of 16, 18, and 29 was more effective than 2 μg/mL of fluconazole at inhibiting fungal growth of the strains tested. The most active compound (16) completely inhibited the growth of C. albicans SC5314 at 16 μg/mL for 24 h, affected biofilm formation and destroyed the mature biofilm at 64 μg/mL. Several Saccharomyces cerevisiae strains, overexpressing recombinant Cyp51s or drug efflux pumps, indicated 16, 18, and 29 targeted Cyp51 without being significantly affected by a common active site mutation, but were susceptible to target overexpression and efflux by both MFS and ABC transporters. GC-MS analysis demonstrated that 16, 18, and 29 interfered with the C. albicans ergosterol biosynthesis pathway by inhibition at Cyp51. Molecular docking studies elucidated the binding modes of 18 with Cyp51. The compounds showed low cytotoxicity, low hemolytic activity and favorable ADMT properties. Importantly, compound 16 showed potent in vivo antifungal efficacy in the G. mellonella infection model. Taken together, this study presents more effective, broad-spectrum, low toxicity triazole analogues that can contribute to the development of novel antifungal agents and help overcome antifungal resistance.

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 anti-fungal activities against eight pathogenic fungi. The most active compounds 13, 20 and 27 displayed outstanding antifungal activity with MIC values ranging from <0.008 mu g/mL to 1 mu g/mL, and showed potent activity against six drug-resistant Candida auris isolates. Growth curve assays further confirmed the high potency of these compounds. Moreover, compounds 13, 20 and 27 showed a potent inhibitory activity on biofilm formation of C. albicans SC5314 and C. neoformans H99. Notably, compound 13 showed no inhibition of human CYP1A2 and low inhibitory activity against CYP2D6 and CYP3A4, suggesting a low risk of drug-drug interactions. With high potency in vitro and in vivo and good safety profiles, compound 13 will be further investigated as a promising candidate.

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 Candida albicans SC5314. Among the 37 nicotinamide derivatives screened, compound 16g was found to be the most active against C. albicans SC5314, with an MIC value of 0.25 μg/mL and without significant cytotoxicity. The rudimentary structure-activity relationships study revealed that the position of the amino and isopropyl groups of 16g was critical for its antifungal activity. In particular, compound 16g showed potent activity against six fluconazole-resistant C. albicans strains with MIC values ranging from 0.125–1 μg/mL and showed moderate activity against the other seven species of Candida, three strains of Cryptococcus neoformans, and three strains of Trichophyton. Furthermore, compound 16g showed fungicidal, anti-hyphal, and anti-biofilm activities in vitro, which were related to its ability to disrupt the cell wall of C. albicans. Taken together, 16g is a promising compound that is fungal-specific by targeting the cell wall and could be used as a lead compound for further investigation.

A series of novel triazole derivatives containing aryl-propanamide side chains was designed and synthesised. In vitro 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 Candida albicans SC5314, Cryptococcus neoformans 22-21, Candida glabrata 537 and Candida parapsilosis 22-20 with MIC values in the range of & LE;0.125 & mu;g/mL-4.0 & mu;g/mL. In addition, compounds A1, A2, A6, A12 and A15 showed inhibitory activities against fluconazole-resistant Candida albicans and Candida auris. Preliminary structure-activity relationships (SARs) are also summarised. Moreover, GC-MS analysis demonstrated that A1, A3, and A9 interfered with the C. albicans ergosterol biosynthesis pathway by inhibiting Cyp51. Molecular docking studies elucidated the binding modes of A3 and A9 with Cyp51. These compounds with low haemolytic activity and favourable ADME/T properties are promising for the development of novel antifungal agents.

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. Of particular note, compounds 6, 22, 28, 30 and 36 were highly active against Candida neoformans 32609 with MIC ≤ 0.125 µg/mL and showed broad-spectrum antifungal activity including against fluconazole-resistant Candida auris 891. In addition, compounds 6 and 22 demonstrated inhibitory effects on filamentation in the azole-resistant C. albicans isolate. Moreover, compounds 6 and 22 were minimally toxic to HUVECs and possessed weak inhibitory effects on the human CYP3A4 and CYP2D6. SARs and docking study further indicated that ortho-substituted groups in the terminal phenyl ring can promote the compounds to improve their antifungal activity.

As an essential part in the toolbox of super-resolution microscopy, stimulated emission depletion (STED) nanoscopy has been widely explored in revealing the substructure and bioactivities in fluorescence imaging. Among the applied STED fluorophores, silicon-substituted rhodamines (SiRs) belong to one of the most extensively employed fluorophores. The carboxy-SiR was favored in STED bioimaging with many advantages, including reliable photostability, cell permeability, tunable fluorogenicity, feasible structural decoration and so on. We reviewed the research of carboxy-SiR in the STED nanoscopy and hopefully this can inspire more efforts in the design and application of STED fluorophores.

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 5k and 6c showed excellent in vitro activities against C. albicans (MIC = 0.125, 0.0625 μg/mL), C. neoformans (MIC = 0.125, 0.0625 μg/mL), and A. fumigatus (MIC = 8.0, 4.0 μg/mL). Compound 6c also exerted superior activity to compound 5k and fluconazole in inhibiting hyphae growth of C. albicans and inhibiting drug-resistant strains of C. albicans, and it could reduce fungal burdens in mice kidney at a dosage of 1.0 mg/kg. An in vivo efficacy evaluation indicated that 6c could effectively protect mice models from C. albicans infection at doses of 0.5, 1.0, and 2.0 mg/kg. These results suggested that compound 6c deserves further investigation.

Cryptococcus neoformans and Cryptococcus gattii 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 P163-0892, which had potent in vitro and in vivo antifungal activity against Cryptococcus spp. In vitro tests showed that P163-0892 was not cytotoxic and had highly selective and strong antifungal activities against Cryptococcus spp. with MIC values less than 1 μg/mL. Synergism of P163-0892 and fluconazole was also observed in vitro. The in vivo antifungal efficacy of P163-0892 was assessed in a wax moth larval fungal infection model, and treatment with 10 mg/kg P163-0892 caused a significant reduction in fungal burden and significant extension of the survival time. Taken together, our data indicate that the hit compound P163-0892 warrants further investigation as a novel anti-Cryptococcus agent.

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 9A16 displayed excellent antifungal and anti-drug-resistant fungal ability (MIC80 = 0.0156-8 μg/mL). In addition, compound 9A16 showed powerful in vivo efficacy on mice systematically infected with Candida albicans SC5314, Cryptococcus neoformans H99, fluconazole-resistant C. albicans 100, and Aspergillus fumigatus 7544. Moreover, compared to fluconazole, compound 9A16 showed better in vitro anti-biofilm activity and was more difficult to induce drug resistance in a 1 month induction of resistance assay in C. albicans. With favorable pharmacokinetics, an acceptable safety profile, and high potency in vitro and in vivo, compound 9A16 is currently under preclinical investigation.