SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents

Haranahalli, Krupanandan; Lazzarini, C.; Sun, Yi; Zambito, Julia; Pathiranage, Senuri; McCarthy, Joanna; Mallamo, John P.; Poeta, Maurizio Del; Ojima, Iwao

doi:10.1021/acs.jmedchem.9b01004

Cited by 25 publications

(21 citation statements)

References 46 publications

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“…Not only did SB-AF-1002 outperform fluconazole, but most importantly, the mice showed an almost complete clearance of cryptococcal cells from the lungs and brains. These results show that this effect is dose dependent, further confirming our previous dose-dependent results obtained using an in vitro killing assay (17). All these results clearly indicate the effectiveness of SB-AF-1002 against cryptococcosis.…”

Section: Discussionsupporting

confidence: 90%

“…In this study, we assessed the in vivo efficacy of the acylhydrazone SB-AF-1002 in different animal models of fungal infections. SB-AF-1002, which was among our top 5 lead compounds previously published, was chosen for an advanced preclinical study for its characteristics of being highly active in vitro against a variety of fungal clinical isolates and for its low toxicity in mammalian cells (17). In this study, we showed that SB-AF-1002 is highly efficacious in animal models of cryptococcosis, candidiasis, and aspergillosis.…”

Section: Discussionmentioning

confidence: 91%

“…These results have further validated the sphingolipid glucosylceramide (GlcCer) pathway to be a highly promising target for antifungal therapy (16). Following up on the encouraging results, we designed and synthesized a library of aromatic acylhydrazones for structure-activity relationship (SAR) studies (17). We identified 5 compounds that are highly potent and selective against several key strains of fungi in vitro.…”

mentioning

confidence: 96%

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Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent

Lazzarini

Haranahalli

McCarthy³

et al. 2020

Antimicrob Agents Chemother

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The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, narrow spectrum of activity, and more importantly for the consistent rise of fungal species that are intrinsically resistant or develop resistance due to the prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, BHBM and D13, we performed a SAR study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified as the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive in vivo activity of 2,4-dibromo-N′-(5-bromo-2-hydroxybenzylidene) benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis and aspergillosis. Specifically, animals treated with SB-AF-1002 survive the infection, but also show a clearing of key organs from fungal cells. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to the parent compound D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents, which warrants further development for the treatment of invasive fungal infections.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 96%

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Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent

Lazzarini

Haranahalli

McCarthy³

et al. 2020

Antimicrob Agents Chemother

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“…If this transport is blocked, IPCs or/and GlcCer synthesis will not occur. Therefore, a drug targeting the transport of vesicles containing ceramide from the ER to the Golgi (e.g., [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (known as BHBM)) will significantly impact the synthesis of complex sphingolipids, even though the compound(s) does not directly inhibit any enzyme involved in the pathway illustrated in Figure 1 [ 29 , 30 , 31 , 32 ]. Similarly, compounds affecting fatty acid elongation, such as minimoidin, may also affect the synthesis of ceramide [ 33 ] because ceramide synthases are only able to incorporate specific fatty acids into DHS and PHS.…”

Section: Drugsmentioning

confidence: 99%

Antifungal Drug Development: Targeting the Fungal Sphingolipid Pathway

McEvoy

Normile

Poeta

2020

JoF

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Fungal infections are becoming more prevalent and problematic due to the continual rise of immune deficient patients as well as the progressive development of drug resistance towards currently available antifungal drugs. There has been a significant increase in the development of antifungal compounds with a similar mechanism of action of current drugs. In contrast, there has been very little progress in developing compounds inhibiting totally new fungal targets or/and fungal pathways. This review focuses on novel compounds recently discovered to target the fungal sphingolipids and their metabolizing enzymes.

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“…Forty-two out of the 200 compounds displayed MIC 80 ≤1 µg/mL. Most of the hit compounds possessed one or more bromine atoms on either of the phenyl rings [53].…”

Section: Discovery Of Fluoro-acylhydrazones As Novel Anti-fungal Agenmentioning

confidence: 99%

Recent progress in the strategic incorporation of fluorine into medicinally active compounds

Haranahalli

Honda

Ojima

2019

Journal of Fluorine Chemistry

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This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to (i) taxoid anticancer agents, (ii) acylhydrazone-based antifungal agents and (iii) inhibitors of matrix metalloproteinase 9 (MMP9) for medicinal chemistry and chemical biology studies. In the case study (i), a series of next-generation fluorotaxoids, bearing m-OCF3 or m-OCF2H group in the C2-benzoate moiety was designed, synthesized and examined for their potencies. A number of these fluorotaxoids possess two orders of magnitude greater potency in different drug-resistant cancer cell lines as compared to paclitaxel. One of these next-generation fluorotaxoids, SB−−121205wasselected for detailed mechanistic study against highly paclitaxel-resistant human breast cancer cell line, MCF-7/PTX, which disclosed a unique mechanism of action. Recently, glucosylceramide (GlcCer) synthesis emerged as a promising target for next-generation antifungal agents, especially against cryptococcosis, candidiasis and pulmonary aspergillosis. The HTP screening of compound libraries identified several acylhydrazones as hit compounds. In the case study (ii), fluoro-acylhydrazones containing F, OCF3, OCHF2, o-F/p-OCF3, as well as o-F/p-CF3 functional groups in the ring A and ring B were designed based on these hit compounds, synthesized and examined for their potencies against C. neoformans. A number of those novel fluoro-acylhydrazones exhibited high potency and excellent killing properties. The hemopexin-like domain of matrix metalloproteinases (MMPs) is a highly promising target to circumvent the critical issue in the development of MMP inhibitors for the treatment of various cancers. In the case study (iii), a small optimization library of compounds, based on the OCHF2-containing hit compound, SB-M-001, was generated and evaluated, which identified a fluorine-containing new lead compound, SB-M-103. SB-M-103 was found to inhibit tumor cell growth, migration, and invasion by effectively disrupting the MMP-9 homodimerization.

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SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents

Cited by 25 publications

References 46 publications

Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent

Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent

Antifungal Drug Development: Targeting the Fungal Sphingolipid Pathway

Recent progress in the strategic incorporation of fluorine into medicinally active compounds

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