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1.
Proc Natl Acad Sci U S A ; 121(2): e2314101120, 2024 Jan 09.
Article in English | MEDLINE | ID: mdl-38165935

ABSTRACT

Mycobacterium abscessus (Mab), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab ΔtetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab ΔtetV. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti-Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections.


Subject(s)
Anti-Infective Agents , Mycobacterium Infections, Nontuberculous , Mycobacterium abscessus , Humans , Animals , Mice , Spectinomycin/pharmacology , Mycobacterium Infections, Nontuberculous/drug therapy , Mycobacterium Infections, Nontuberculous/microbiology , Anti-Bacterial Agents/pharmacology , Nontuberculous Mycobacteria , Anti-Infective Agents/pharmacology , Ethylenes/pharmacology , Microbial Sensitivity Tests
2.
Antimicrob Agents Chemother ; : e0071624, 2024 Sep 30.
Article in English | MEDLINE | ID: mdl-39345140

ABSTRACT

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

3.
Bioorg Med Chem Lett ; 112: 129934, 2024 Nov 01.
Article in English | MEDLINE | ID: mdl-39214506

ABSTRACT

Spectinamides are a novel class of narrow-spectrum antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Spectinamide 1810 has shown a good safety record following subcutaneous injection in mice or infusion in rats but exhibits transient acute toxicity following bolus administration in either species. To improve the therapeutic index of 1810, an injectable prodrug strategy was explored. The injectable phosphate prodrug 3408 has a superior maximum tolerated dose compared to 1810 or Gentamicin. Following intravenous administration in rodents, prodrug 3408 was quickly converted to 1810. The resulting 1810 exposure and pharmacokinetic profile after 3408 administration was identical to equivalent molar amounts of 1810 given directly by intravenous administration. 3408 and the parent 1810 exhibited similar overall efficacy in a BALB/c acute tuberculosis efficacy model. Delivery of 1810 in phosphate prodrug form, therefore, holds the potential to improve further the therapeutic index of an already promising tuberculosis antibiotic.


Subject(s)
Antitubercular Agents , Mice, Inbred BALB C , Prodrugs , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Prodrugs/chemistry , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacokinetics , Mice , Rats , Microbial Sensitivity Tests , Spectinomycin/pharmacology , Spectinomycin/chemical synthesis , Spectinomycin/chemistry , Phosphates/chemistry , Phosphates/pharmacology , Phosphates/chemical synthesis , Mycobacterium tuberculosis/drug effects , Molecular Structure , Dose-Response Relationship, Drug , Structure-Activity Relationship
4.
Bioorg Med Chem ; 101: 117609, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38364599

ABSTRACT

In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50 = 17.3 nM, MDA-MB-361 IC50 = 8.4 nM, and MV4-11 IC50 = 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 µL·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-t = 657 ng·h·mL-1, oral bioavailability of 21.4 %) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.


Subject(s)
Antineoplastic Agents , Neoplasms , Protein Kinase Inhibitors , Animals , Rats , Antineoplastic Agents/pharmacology , Antineoplastic Agents/metabolism , Cell Cycle Proteins , Cell Line, Tumor , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Neoplasms/drug therapy , Nuclear Proteins/metabolism , Rats, Sprague-Dawley , Structure-Activity Relationship , Transcription Factors , Bromodomain Containing Proteins/antagonists & inhibitors , Indoles/chemistry , Indoles/pharmacology , Polo-Like Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology
5.
J Org Chem ; 88(7): 4162-4171, 2023 Apr 07.
Article in English | MEDLINE | ID: mdl-36971317

ABSTRACT

This paper reports the efficient synthesis of substituted (Z)-N-allyl sulfonamides via a palladium-catalyzed three-component tandem reaction of N-buta-2,3-dienyl sulfonamides with iodides and sulfonyl hydrazide or sulfinic acid sodium salt as nucleophiles. Pd(PPh3)4 (2.5 mol %), K2CO3, and THF were used as the optimal catalyst, base, and solvent, respectively. The substituted (Z)-N-allyl sulfonamides were obtained in a 30-83% overall yield. Mechanistic investigations revealed that the formation of the single (Z)-isomer was controlled by the formation of a six-membered palladacycle intermediate.

6.
Bioorg Chem ; 140: 106738, 2023 11.
Article in English | MEDLINE | ID: mdl-37562315

ABSTRACT

Phosphoinositide 3-kinase (PI3K) was an important cellular signal transducer, while PI3Kα was the most mutated family member in cancer. Selective PI3Kα inhibitors have become the frequent research in recent years because of their excellent curative effect and reduced side effects. Here, we described a series of PI3Kα inhibitors with 1,3,5-triazine or pyrimidine skeleton containing benzoyl hydrazine based on the pan-PI3K inhibitor ZSTK474 relying on the strategies of structure-based drug discovery (SBDD) and computer-aided drug design (CADD). Among them, compound F8 exhibited improved selective PI3Kα inhibition with an IC50 value of 0.14 nM and more significant anti-proliferative activities against three tumor-derived cell lines (PC-3 IC50 = 0.28 µM, HCT-116 IC50 = 0.57 µM, and U87-MG IC50 = 1.37 µM) than ZSTK-474. Compound F-8 induced a great decrease in mitochondrial membrane which caused cell cycle arrest at G1 phase and apoptosis in U87-MG cells in a dose-dependent manner. Furthermore, compound F8 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line with no clear evidence of toxicity following intraperitoneal injection of 40 mg/kg. Compound F8 may serve as a PI3Kα-selective inhibitor and provided the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.


Subject(s)
Antineoplastic Agents , Phosphatidylinositol 3-Kinases , Humans , Mice , Animals , Phosphatidylinositol 3-Kinases/metabolism , Antineoplastic Agents/pharmacology , Cell Proliferation , Cell Line, Tumor , Phosphatidylinositol 3-Kinase , Drug Design , Hydrazines/pharmacology , Pyrimidines/pharmacology , Drug Screening Assays, Antitumor , Structure-Activity Relationship
7.
Bioorg Chem ; 130: 106211, 2023 01.
Article in English | MEDLINE | ID: mdl-36343598

ABSTRACT

Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), three series of novel 1,3,5-triazine or pyrimidine derivatives containing semicarbazones have been designed and synthesized to obtain new potent and selective PI3Kα inhibitors. Their inhibitory activities in vitro were evaluated against PI3Kα and three tumor-derived cell lines (U87-MG, MCF-7, and PC-3). We also tested promising compounds (A4, A6, A10, and B1) for other PI3K class I subtype (PI3Kß, PI3Kδ, and PI3Kγ) activity. The representative compound A10 exhibited an IC50 value of 0.32 nM against PI3Kα, and demonstrated extraordinary subtype selectivity. Furthermore, compound A10 obviously inhibited proliferation of MCF-7 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, and arrested G2 phase in a dose-dependent manner. Additionally, compound A10 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line without an obvious sign of toxicity upon 20 mg/kg oral administration. Compound A10 may serve as a PI3Kα-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.


Subject(s)
Antineoplastic Agents , Humans , Mice , Animals , Phosphoinositide-3 Kinase Inhibitors , Structure-Activity Relationship , Cell Proliferation , Antineoplastic Agents/pharmacology , Triazines/pharmacology , Cell Line, Tumor , Benzimidazoles/pharmacology , Drug Design , Drug Screening Assays, Antitumor
8.
Antimicrob Agents Chemother ; 65(11): e0174420, 2021 10 18.
Article in English | MEDLINE | ID: mdl-34424046

ABSTRACT

Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of antituberculosis agents, and the lead spectinamide 1810 has demonstrated excellent efficacy, safety, and drug-like properties in numerous in vitro and in vivo assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of Mycobacterium tuberculosis infection and in healthy animals. The obtained data on 1810 plasma concentrations and counts of CFU in lungs were analyzed using a population pharmacokinetic/pharmacodynamic (PK/PD) approach as well as classical anti-infective PK/PD indices. The analysis results indicate that there was no difference in the PK of 1810 in infected compared to healthy, uninfected animals. The PK/PD index analysis showed that bacterial killing of 1810 in mice was best predicted by the ratio of maximum free drug concentration to MIC (fCmax/MIC) and the ratio of the area under the free concentration-time curve to the MIC (fAUC/MIC) rather than the cumulative percentage of time that the free drug concentration is above the MIC (f%TMIC). A novel PK/PD model with consideration of postantibiotic effect could adequately describe the exposure-response relationship for 1810 and supports the notion that the in vitro observed postantibiotic effect of this spectinamide also translates to the in vivo situation in mice. The obtained results and pharmacometric model for the exposure-response relationship of 1810 provide a rational basis for dose selection in future efficacy studies of this compound against M. tuberculosis.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Animals , Anti-Bacterial Agents , Antitubercular Agents/pharmacology , Disease Models, Animal , Mice , Microbial Sensitivity Tests , Tuberculosis/drug therapy
9.
Article in English | MEDLINE | ID: mdl-33139282

ABSTRACT

Phenotypic screening of inhibitors of the essential Mycobacterium tuberculosis FAS-II dehydratase HadAB led to the identification of GSK3011724A, a compound previously reported to inhibit the condensation step of FAS-II. Whole-cell-based and cell-free assays confirmed the lack of activity of GSK3011724A against the dehydratase despite evidence of cross-resistance between GSK3011724A and HadAB inhibitors. The nature of the resistance mechanisms is suggestive of alterations in the FAS-II interactome reducing access of GSK3011724A to KasA.


Subject(s)
Mycobacterium tuberculosis , Bacterial Proteins/genetics , Fatty Acid Synthase, Type II , Mycolic Acids
10.
Bioconjug Chem ; 31(11): 2564-2575, 2020 11 18.
Article in English | MEDLINE | ID: mdl-33070611

ABSTRACT

Ligands for cereblon, a component of a functional E3 ligase complex that targets proteins for proteolysis, are critical for developing molecular glues and proteolysis-targeting chimeras (PROTACs), which have therapeutic implications for various diseases. However, the lack of sensitivity of previously reported assays limits characterization of cereblon ligands. To address this shortcoming, we developed BODIPY FL thalidomide (10) as a high-affinity fluorescent probe for the human cereblon protein, with a Kd value of 3.6 nM. We then used BODIPY FL thalidomide (10) to develop a cereblon time-resolved fluorescence resonance energy transfer (TR-FRET) binding assay. The IC50 values of the cereblon ligand pomalidomide (8) were 6.4 nM in our cereblon TR-FRET binding assay, 264.8 nM in a previously reported Cy5-conjugated thalidomide (7)-mediated fluorescence polarization (FP) assay, and 1.2 µM in a previously reported Cy5-conjugated cereblon modulator (compound 7) (9)-mediated TR-FRET assay, indicating that our cereblon TR-FRET binding assay is 41- and 187-fold more sensitive than these two previously published assays. With our cereblon TR-FRET binding assay, we detected binding of cereblon ligands but not binding of bromodomain-containing protein 4 or von Hippel-Lindau ligands, thereby demonstrating its selectivity. Our cereblon TR-FRET binding assay was very stable and detected changes in phthalimide activity due to thalidomide isomerization. Therefore, the BODIPY FL thalidomide (10)-mediated cereblon TR-FRET binding assay we designed is highly sensitive, selective, and stable and will aid the development and characterization of novel cereblon ligands.


Subject(s)
Adaptor Proteins, Signal Transducing/analysis , Boron Compounds/chemistry , Fluorescence Resonance Energy Transfer/methods , Fluorescent Dyes/chemistry , Thalidomide/chemistry , Ubiquitin-Protein Ligases/analysis , Ligands
11.
Bioorg Med Chem ; 28(9): 115433, 2020 05 01.
Article in English | MEDLINE | ID: mdl-32199690

ABSTRACT

The calpains are a conserved family of cysteine proteases that includes several isoforms of which µ-calpain and m-calpain are the most widely distributed in mammalian cells. Calpains have been implicated in normal physiological processes as well as cellular abnormalities such as neurodegenerative disorders, cataract, and cancer. Therefore, calpain inhibitors are of interest as potential therapeutic agents. We have synthesized four new sulfonamide-based peptidomimetic compounds 2-5 as inhibitors of µ-calpain that incorporate (E)-1-(phenyl)-2-phenyldiazene and (E)-1-(phenyl)-2-phenylethene functionalities as the N-terminal capping groups of the inhibitors. Compound 5 with Ki value of 9 nM versus µ-calpain was the most potent member of the group. The compounds were predicted to be more lipophilic compared to MDL28170 based on CLogP estimation. They displayed moderate to good antiproliferative activity versus melanoma cell lines (A-375 and B-16F1) and PC-3 prostate cancer cells in vitro. Additionally, one member of the group (compound 3) inhibited DU-145 cell invasion by 80% at 2 µM concentration in the Matrigel cell invasion assay.


Subject(s)
Antineoplastic Agents/pharmacology , Glycoproteins/pharmacology , Peptidomimetics/pharmacology , Sulfonamides/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glycoproteins/chemical synthesis , Glycoproteins/chemistry , Humans , Molecular Structure , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Tumor Cells, Cultured
12.
Pharm Res ; 36(9): 136, 2019 Jul 18.
Article in English | MEDLINE | ID: mdl-31321552

ABSTRACT

PURPOSE: Human tuberculosis (TB) is a global health problem that causes nearly 2 million deaths per year. Anti-TB therapy exists, but it needs to be administered as a cocktail of antibiotics for six months. This lengthy therapy results in low patient compliance and is the main reason attributable to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. METHODS: One alternative approach is to combine anti-TB multidrug therapy with inhalational TB therapy. The aim of this work was to develop and characterize dry powder formulations of spectinamide 1599 and ensure in vitro and in vivo delivered dose reproducibility using custom dosators. RESULTS: Amorphous dry powders of spectinamide 1599 were successfully spray dried with mass median aerodynamic diameter (MMAD) = 2.32 ± 0.05 µm. The addition of L-leucine resulted in minor changes to the MMAD (1.69 ± 0.35 µm) but significantly improved the inhalable portion of spectinamide 1599 while maintaining amorphous qualities. Additionally, we were able to demonstrate reproducibility of dry powder administration in vitro and in vivo in mice. CONCLUSIONS: The corresponding systemic drug exposure data indicates dose-dependent exposure in vivo in mice after dry powder intrapulmonary aerosol delivery in the dose range 15.4 - 32.8 mg/kg.


Subject(s)
Antitubercular Agents/pharmacokinetics , Dry Powder Inhalers/methods , Spectinomycin/analogs & derivatives , Administration, Inhalation , Aerosols , Animals , Antitubercular Agents/administration & dosage , Drug Delivery Systems , Drug Liberation , Drug Resistance, Multiple, Bacterial , Female , Mice, Inbred BALB C , Mycobacterium tuberculosis/drug effects , Particle Size , Powders , Reproducibility of Results , Spectinomycin/administration & dosage , Spectinomycin/pharmacokinetics
13.
Proc Natl Acad Sci U S A ; 113(26): 7148-53, 2016 06 28.
Article in English | MEDLINE | ID: mdl-27307435

ABSTRACT

Trehalose is a disaccharide essential for the survival and virulence of pathogenic fungi. The biosynthesis of trehalose requires trehalose-6-phosphate synthase, Tps1, and trehalose-6-phosphate phosphatase, Tps2. Here, we report the structures of the N-terminal domain of Tps2 (Tps2NTD) from Candida albicans, a transition-state complex of the Tps2 C-terminal trehalose-6-phosphate phosphatase domain (Tps2PD) bound to BeF3 and trehalose, and catalytically dead Tps2PD(D24N) from Cryptococcus neoformans bound to trehalose-6-phosphate (T6P). The Tps2NTD closely resembles the structure of Tps1 but lacks any catalytic activity. The Tps2PD-BeF3-trehalose and Tps2PD(D24N)-T6P complex structures reveal a "closed" conformation that is effected by extensive interactions between each trehalose hydroxyl group and residues of the cap and core domains of the protein, thereby providing exquisite substrate specificity. Disruption of any of the direct substrate-protein residue interactions leads to significant or complete loss of phosphatase activity. Notably, the Tps2PD-BeF3-trehalose complex structure captures an aspartyl-BeF3 covalent adduct, which closely mimics the proposed aspartyl-phosphate intermediate of the phosphatase catalytic cycle. Structures of substrate-free Tps2PD reveal an "open" conformation whereby the cap and core domains separate and visualize the striking conformational changes effected by substrate binding and product release and the role of two hinge regions centered at approximately residues 102-103 and 184-188. Significantly, tps2Δ, tps2NTDΔ, and tps2D705N strains are unable to grow at elevated temperatures. Combined, these studies provide a deeper understanding of the substrate recognition and catalytic mechanism of Tps2 and provide a structural basis for the future design of novel antifungal compounds against a target found in three major fungal pathogens.


Subject(s)
Candida albicans/enzymology , Cryptococcus neoformans/enzymology , Fungal Proteins/chemistry , Phosphoric Monoester Hydrolases/chemistry , Biocatalysis , Candida albicans/chemistry , Candida albicans/genetics , Candida albicans/metabolism , Cryptococcus neoformans/chemistry , Cryptococcus neoformans/genetics , Fungal Proteins/genetics , Fungal Proteins/metabolism , Gene Expression Regulation, Fungal , Phosphoric Monoester Hydrolases/genetics , Phosphoric Monoester Hydrolases/metabolism , Substrate Specificity , Sugar Phosphates/chemistry , Sugar Phosphates/metabolism , Trehalose/analogs & derivatives , Trehalose/chemistry , Trehalose/metabolism
14.
J Antimicrob Chemother ; 72(3): 770-777, 2017 03 01.
Article in English | MEDLINE | ID: mdl-27999020

ABSTRACT

Objectives: New drug regimens employing combinations of existing and experimental antimicrobial agents are needed to shorten treatment of tuberculosis (TB) in humans. The spectinamides are narrow-spectrum semisynthetic analogues of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead 1599, have been previously shown to exhibit a promising therapeutic profile in mice as single agents. Here we explore the in vivo activity of lead spectinamides when combined with other agents. Methods: The efficacy of 1599 or 1810 was tested in combination in three increasingly advanced TB mouse models. Mice were infected by aerosol and allowed to establish acute or chronic infection, followed by treatment (≤4 weeks) with the spectinamides alone or in two- and three-drug combination regimens with existing and novel therapeutic agents. Bacteria were enumerated from lungs by plating for cfu. Results: Herein we show the following: (i) 1599 exhibits additive or synergistic activity with most of the first-line agents; (ii) 1599 in combination with rifampicin and pyrazinamide or with bedaquiline and pyrazinamide promotes significantly improved efficacy in the high-dose aerosol model; (iii) 1599 enhances efficacy of rifampicin or pyrazinamide in chronically infected BALB/c mice; and (iv) 1599 is synergistic when administered in combination with rifampicin and pyrazinamide in the C3HeB/FeJ mouse model showing caseous necrotic pulmonary lesions. Conclusions: Spectinamides were effective partner agents for multiple anti-TB agents including bedaquiline, rifampicin and pyrazinamide. None of these in vivo synergistic interactions was predicted from in vitro MIC chequerboard assays. These data support further development of the spectinamides as combination partners with existing and experimental anti-TB agents.


Subject(s)
Antitubercular Agents/therapeutic use , Spectinomycin/chemistry , Spectinomycin/therapeutic use , Tuberculosis/drug therapy , Animals , Disease Models, Animal , Drug Synergism , Drug Therapy, Combination , Lung/drug effects , Lung/microbiology , Mice , Mice, Inbred BALB C , Mycobacterium tuberculosis/drug effects , Pyrazinamide/therapeutic use , Quinolines/therapeutic use , Rifampin/therapeutic use , Tuberculosis/microbiology
15.
Bioorg Med Chem Lett ; 26(2): 388-391, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26711150

ABSTRACT

Pretomanid (PA-824) is an important nitroimidazole antitubercular agent in late stage clinical trials. However, pretomanid is limited by poor solubility and high protein binding, which presents opportunities for improvement in its physiochemical properties. Conversely, the oxazolidinone linezolid has excellent physicochemical properties and has recently shown impressive activity for the treatment of drug resistant tuberculosis. In this study we explore if incorporation of the outer ring elements found in first and second generation oxazolidinones into the nitroimidazole core of pretomanid can be used to improve its physicochemical and antitubercular properties. The synthesis of pretomanid outer oxazolidinone ring hybrids was successfully performed producing hybrids that maintained antitubercular activity and had improved in vitro physicochemical properties. Three lead compounds were identified and evaluated in a chronic model of tuberculosis infection in mice. However, the compounds lacked efficacy suggesting that portions of PA-824 tail not found in the hybrid molecules are required for in vivo efficacy.


Subject(s)
Antitubercular Agents/therapeutic use , Mycobacterium tuberculosis/drug effects , Nitroimidazoles/therapeutic use , Oxazolidinones/therapeutic use , Tuberculosis/drug therapy , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Chronic Disease , Disease Models, Animal , Mice , Mice, Inbred C57BL , Nitroimidazoles/chemical synthesis , Nitroimidazoles/chemistry , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry
16.
Phys Chem Chem Phys ; 18(13): 9176-85, 2016 Apr 07.
Article in English | MEDLINE | ID: mdl-26974060

ABSTRACT

The design and synthesis of unique novel heterostructures for high-performance photocatalytic activity has exerted a tremendous fascination and has recently attracted intensive attention. In this work, a branch-like α-Fe2O3/TiO2 heterostructure has been synthesized controllably through an electrospinning method combined with a hydrothermal approach. The backbone of the heterostructure is composed of a 3D porous TiO2 nanofiber (∼70 nm in diameter) network with plenty of α-Fe2O3 nanorods (100-200 nm in length) deposited on them. The novel branch-like nanocomposites have an abundantly porous structure as well as large surface areas (up to 42.8 m(2) g(-1)). In addition, their visible light photodegradation behaviour towards organic dyes, including Congo red (CR), methylene blue (MB), eosin red (ER) and methyl orange (MO), was investigated. Their excellent photocatalytic performances are attributed to their large surfaces, improved visible light absorption and high separation efficiency of the photogenerated electrons/holes. Furthermore, the degradation process was further studied by varying the amount of α-Fe2O3 deposited. The sample α-Fe2O3/TiO2-3 possessed the best performance to efficiently decolor CR solution even at a high concentration of 50 mg L(-1) (160 min, 94 mg g(-1)), ascribed to the high adsorption capacity derived from the large surface, strong electrostatic interaction and structural match between α-Fe2O3/TiO2-3 and CR. These α-Fe2O3/TiO2 heterostructures exhibit great potential for decontamination of organic pollutants in waste water under visible light.

17.
Bioconjug Chem ; 25(9): 1664-77, 2014 Sep 17.
Article in English | MEDLINE | ID: mdl-25133934

ABSTRACT

The pregnane X receptor (PXR) regulates the metabolism and excretion of xenobiotics and endobiotics by regulating the expression of drug-metabolizing enzymes and transporters. The unique structure of PXR allows it to bind many drugs and drug leads, possibly causing undesired drug-drug interactions. Therefore, it is crucial to evaluate whether chemicals or drugs bind to PXR. Fluorescence-based assays are preferred because of their sensitivity and nonradioactive nature. On the basis of our previously characterized 4 (BODIPY FL vinblastine), a high-affinity PXR probe, we developed 20 (BODIPY FL vindoline) and showed that it is a novel and potent PXR fluorescent probe with Kd of 256 nM in a time-resolved fluorescence resonance energy transfer (TR-FRET) binding assay with PXR. By using 20 (BODIPY FL vindoline) in the PXR TR-FRET assay, we obtained a more than 7-fold signal-to-background ratio and high signal stability (signal was stable for at least 120 min, and Z'-factor > 0.85 from 30 to 240 min). The assay can tolerate DMSO up to 2%. This assay has been used to evaluate a panel of PXR ligands for their PXR-binding affinities. The performance of 20 (BODIPY FL vindoline) in the PXR TR-FRET assay makes it an ideal PXR fluorescent probe, and the newly developed PXR TR-FRET assay with 20 (BODIPY FL vindoline) as a fluorescent probe is suitable for high-throughput screening to identify PXR-binding ligands.


Subject(s)
Boron Compounds/chemistry , Boron Compounds/metabolism , Drug Design , Fluorescent Dyes/chemistry , Fluorescent Dyes/metabolism , Receptors, Steroid/metabolism , Vinblastine/analogs & derivatives , Dimethyl Sulfoxide/chemistry , Humans , Pregnane X Receptor , Protein Structure, Tertiary , Receptors, Steroid/chemistry , Vinblastine/chemistry
18.
bioRxiv ; 2024 May 13.
Article in English | MEDLINE | ID: mdl-38798577

ABSTRACT

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. To demonstrate that this translates to more effective cure, we first confirmed the role of rifampin, with or without pyrazinamide, as essential to achieve effective bactericidal responses and sterilizing cure in the current standard of care regimen in chronically infected C3HeB/FeJ mice compared to BALB/c mice. Thus, demonstrating added value in testing clinically relevant regimens in murine models of increasing pathologic complexity. Next we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models including mice exhibiting advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

19.
ACS Med Chem Lett ; 14(9): 1266-1274, 2023 Sep 14.
Article in English | MEDLINE | ID: mdl-37736169

ABSTRACT

Recent studies have shown that phosphoinositide 3-kinase (PI3K) plays a vital role in cell division, and it has become a therapeutic target for many cancers. In this paper, some new 1,3,5-triazine or pyrimidine skeleton derivatives containing dithiocarbamate were designed and synthesized based on the reasonable drug design strategy from the previously effective compound 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK-474), in order to get effective selective PI3Kα inhibitors that have not been reported in the literature. In addition, the inhibitory activities of these compounds on PI3Kα and two tumor cell lines in vitro (HCT-116, U87-MG) were evaluated. The representative compound 13 showed a half-maximal inhibitory concentration (IC50) value of 1.2 nM for PI3Kα and an exciting kinase selectivity. Compound 13 displayed strong efficacy in HCT-116 and U87-MG cell lines with IC50 values of 0.83 and 1.25 µM, respectively. In addition, compound 13 induced obvious tumor regression in the U87-MG cell line xenografts mouse model, with no obvious signs of toxicity after intraperitoneal injection at a dose of 40 mg/kg. Compound 13 can be an effective selective inhibitor of PI3Kα, and it provides patients with an opportunity to avoid the side effects related to the wider inhibition of the class I PI3K family.

20.
Eur J Med Res ; 28(1): 570, 2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38053192

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD), two common irreversible neurodegenerative diseases, share similar early stage syndromes, such as olfaction dysfunction. Yet, the potential comorbidity mechanism of AD and PD was not fully elucidated. METHODS: The gene expression profiles of GSE5281 and GSE8397 were downloaded from the Gene Expression Omnibus (GEO) database. We utilized a series of bioinformatics analyses to screen the overlapped differentially expressed genes (DEGs). The hub genes were further identified by the plugin CytoHubba of Cytoscape and validated in the hippocampus (HIP) samples of APP/PS-1 transgenic mice and the substantial nigra (SN) samples of A53T transgenic mice by real-time quantitative polymerase chain reaction (RT-qPCR). Meanwhile, the expression of the target genes in the olfactory epithelium/bulb was detected by RT-qPCR. Finally, molecular docking was used to screen potential compounds for the target gene. RESULTS: One hundred seventy-four overlapped DEGs were identified in AD and PD. Five of the top ten enrichment pathways mainly focused on the synapse. Five hub genes were identified and further validated. As a common factor in AD and PD, the changes of synaptosomal-associated protein 25 (SNAP25) mRNA in olfactory epithelium/bulb were significantly decreased and had a strong association with those in the HIP and SN samples. Pazopanib was the optimal compound targeting SNAP25, with a binding energy of - 9.2 kcal/mol. CONCLUSIONS: Our results provided a theoretical basis for understanding the comorbidity mechanism of AD and PD and highlighted that SNAP25 in the olfactory epithelium may serve as a potential target for early detection and intervention in both AD and PD.


Subject(s)
Alzheimer Disease , Parkinson Disease , Animals , Mice , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Gene Expression Profiling , Mice, Transgenic , Molecular Docking Simulation , Parkinson Disease/genetics , Synaptosomal-Associated Protein 25/genetics
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