ABSTRACT
Aim: The purpose of this study is to design and synthesize a series of novel chalcone amide α-glucosidase (AG) inhibitors (L1-L10) based on virtual screening and molecular dynamics (MD) simulation. Materials & methods: Target compounds (L1-L10) were synthesized from 2-hydroxyacetophenone and methyl 4-formylbenzoate. Results: In vitro activity test shows that most compounds have good AG inhibition. Specially, compound L4 (IC50 = 8.28 ± 0.04 µM) had the best inhibitory activity, superior to positive control acarbose (IC50 = 8.36 ± 0.02 µM). Molecular docking results show that the good potency of L4 maybe attributed to strong interactions between chalcone skeleton and active site, and the torsion of carbon nitrogen bond in amide group. Conclusion: Compound L4 maybe regard as a good anti-Type II diabetes candidate to preform further study.
[Box: see text].
Subject(s)
Amides , Drug Design , Glycoside Hydrolase Inhibitors , Molecular Docking Simulation , alpha-Glucosidases , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , alpha-Glucosidases/metabolism , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Humans , Molecular Dynamics Simulation , Chalcone/chemistry , Chalcone/pharmacology , Chalcone/chemical synthesisABSTRACT
Selective cleavage of amide bonds holds prominent significance by facilitating precise manipulation of biomolecules, with implications spanning from basic research to therapeutic interventions. However, achieving selective cleavage of amide bonds via mild synthetic chemistry routes poses a critical challenge. Here, we report a novel amide bond-cleavage reaction triggered by Na[AuCl4] in mild aqueous conditions, where a crucial cyclization step leads to the formation of a 5-membered ring intermediate that rapidly hydrolyses to release the free amine in high yields. Notably, the reaction exhibits remarkable site-specificity to cleave peptide bonds at the C-terminus of allyl-glycine. The strategic introduction of a leaving group at the allyl position facilitated a dual-release approach through π-acid catalyzed substitution. This reaction was employed for the targeted release of the cytotoxic drug monomethyl auristatin E in combination with an antibody-drug conjugate in cancer cells. Finally, Au-mediated prodrug activation was shown in a colorectal zebrafish xenograft model, leading to a significant increase in apoptosis and tumor shrinkage. Our findings reveal a novel metal-based cleavable reaction expanding the utility of Au complexes beyond catalysis to encompass bond-cleavage reactions for cancer therapy.
Subject(s)
Amides , Antineoplastic Agents , Prodrugs , Zebrafish , Animals , Amides/chemistry , Humans , Prodrugs/chemistry , Prodrugs/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Oligopeptides/chemistry , Cell Line, Tumor , Gold/chemistry , Apoptosis/drug effects , Molecular Structure , Immunoconjugates/chemistryABSTRACT
Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.
Subject(s)
Amides , Antineoplastic Agents , Cell Proliferation , Drug Design , Enzyme Inhibitors , Monoacylglycerol Lipases , Monoacylglycerol Lipases/antagonists & inhibitors , Monoacylglycerol Lipases/metabolism , Humans , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Structure-Activity Relationship , Cell Line, Tumor , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Molecular Structure , Drug Screening Assays, Antitumor , Naphthalenes/pharmacology , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Dose-Response Relationship, Drug , Molecular Docking SimulationABSTRACT
Resistant weeds severely threaten crop yields as they compete with crops for resources required for survival. Trifludimoxazin, a protoporphyrinogen IX oxidase (PPO) inhibitor, can effectively control resistant weeds. However, its crop safety record is unsatisfactory. Consequently, a scaffold-hopping strategy is employed in this study to develop a series of new triazinone derivatives featuring an amide structure. Most compounds depicted excellent herbicidal activity across a broad spectrum at 37.5-150 g ai/ha, among which (R)-I-5 was equivalent to flumioxazin. (R)-I-5 demonstrated significant crop tolerance to rice and wheat, even at 150 g ai/ha. (R)-I-5 exhibited superior pharmacokinetic features compared to flumioxazin and trifludimoxazin. This was depicted by the absorption, distribution, metabolism, excretion, and toxicity predictions. Notably, proteomics-based analysis was applied for the first time to investigate variations among plant proteins before and after herbicide application, shedding light on the conservative and divergent roles of PPO.
Subject(s)
Amides , Enzyme Inhibitors , Herbicides , Plant Weeds , Proteomics , Protoporphyrinogen Oxidase , Triazines , Protoporphyrinogen Oxidase/antagonists & inhibitors , Protoporphyrinogen Oxidase/metabolism , Protoporphyrinogen Oxidase/chemistry , Herbicides/chemistry , Herbicides/pharmacology , Herbicides/chemical synthesis , Plant Weeds/drug effects , Triazines/chemistry , Triazines/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Amides/chemistry , Amides/pharmacology , Plant Proteins/chemistry , Plant Proteins/antagonists & inhibitors , Plant Proteins/metabolism , Drug Design , Structure-Activity Relationship , Triticum/chemistry , Oryza/chemistry , Oryza/metabolism , Molecular StructureABSTRACT
Aryl oxalamides are constituents of various promising drug-like molecules. Their aryl groups are derived from the benzenoid aromatic moiety. However, non-benzenoid aromatic molecules, troponoids, are found in various bioactive natural products. It would be thought-provoking to explore non-benzenoid aryl oxalamide derivatives. This report describes the synthesis of N-troponyl-oxalamide peptides by Pd(II)-catalyzed C(sp3)-H functionalization of N-troponyl glycinate peptides. This is the first instance of ß-hydride elimination at the palladium complex of N-troponyl glycinates that generates imine in situ, rendering the synthesis of oxalamides. Importantly, the crystal structures of representative oxalamide derivatives form distinctive foldameric structures, such as ß-sheet type structures, owing to the presence of additional troponyl carbonyl groups. Hence, these non-benzenoid oxalamides are potential scaffolds for tuning the structure and function of N-troponyl peptides, which could provide innovative avenues of research in the development of emerging structural and functional peptides.
Subject(s)
Palladium , Peptides , Catalysis , Palladium/chemistry , Peptides/chemistry , Peptides/chemical synthesis , Amides/chemistry , Amides/chemical synthesis , Models, Molecular , Molecular StructureABSTRACT
During the pandemic, Favipiravir (FVP) and Molnupiravir (MPV) have been widely used for COVID-19 treatment, leading to their presence in the environment. A green synchronous spectrofluorimetric method was developed to simultaneously detect them in environmental water, human plasma, and binary mixtures. Maximum fluorescence intensity was achieved at pH 8, with MPV exhibiting two peaks at 300 and 430 nm, and FVP showing one peak at 430 nm. A fluorescence subtraction method effectively removed interference, enabling direct determination of MPV at 300 nm and FVP at 430 nm. The method showed linearity within 2-13 ng/mL for FVP and 50-600 ng/mL for MPV, with recoveries of 100.35% and 100.12%, respectively. Limits of detection and quantification were 0.19 and 0.57 ng/mL for FVP and 10.52 and 31.88 ng/mL for MPV. Validation according to ICH and FDA guidelines yielded acceptable results. The method demonstrated good recoveries of FVP and MPV in pharmaceuticals, tap water and Nile water (99.62% ± 0.96% and 99.69% ± 0.64%) as per ICH guidelines and spiked human plasma (94.87% ± 2.111% and 94.79% ± 1.605%) following FDA guidelines, respectively. Its environmental friendliness was assessed using Green Analytical Procedure Index (GAPI) and the Analytical Greenness Metric (AGREE) tools.
Subject(s)
Amides , Antiviral Agents , Pyrazines , Spectrometry, Fluorescence , Pyrazines/analysis , Pyrazines/blood , Pyrazines/chemistry , Amides/analysis , Amides/chemistry , Amides/blood , Spectrometry, Fluorescence/methods , Humans , Antiviral Agents/analysis , Antiviral Agents/blood , Uridine/analysis , Uridine/blood , Limit of Detection , Cytidine/analysis , Cytidine/blood , Cytidine/analogs & derivatives , COVID-19 Drug Treatment , Mercaptopurine/blood , Mercaptopurine/analysis , SARS-CoV-2 , HydroxylaminesABSTRACT
In this work, we performed anti-proliferative assays for the compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) on breast cancer (BC) cells (MCF-7, SKBR3, and triple-negative BC (TNBC) MDA-MB-231 cells) to explore its pharmacological mechanism regarding the type of cell death associated with G protein-coupled estrogen receptor (GPER) expression. The results show that HO-AAVPA induces cell apoptosis at 5 h or 48 h in either estrogen-dependent (MCF-7) or -independent BC cells (SKBR3 and MDA-MB-231). At 5 h, the apoptosis rate for MCF-7 cells was 68.4% and that for MDA-MB-231 cells was 56.1%; at 48 h, that for SKBR3 was 61.6%, that for MCF-7 cells was 54.9%, and that for MDA-MB-231 (TNBC) was 43.1%. HO-AAVPA increased the S phase in MCF-7 cells and reduced the G2/M phase in MCF-7 and MDA-MB-231 cells. GPER expression decreased more than VPA in the presence of HO-AAVPA. In conclusion, the effects of HO-AAVPA on cell apoptosis could be modulated by epigenetic effects through a decrease in GPER expression.
Subject(s)
Apoptosis , Breast Neoplasms , Cell Cycle Checkpoints , Receptors, Estrogen , Receptors, G-Protein-Coupled , Humans , Apoptosis/drug effects , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, Estrogen/metabolism , Female , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Cycle Checkpoints/drug effects , MCF-7 Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Amides/pharmacology , Amides/chemistryABSTRACT
A four-step synthesis of the natural product pseudane IX, starting from 3-oxododecanoic acid phenylamide and including only one chromatographic purification, was accomplished with an overall yield of 52%. The same synthetic sequence, but with a controlled partial reduction of a nitro group in the penultimate intermediate, led to the N-oxide of pseudane IX (NQNO). A shortened three-step variation of the synthesis allowed for the preparation of novel carboxamide analogs of the natural product. An agar diffusion assay against six different bacterial strains revealed significant antibacterial activity of the novel analogs against S. aureus at a concentration of 100 µg/mL. One of the novel compounds showed a remarkably broad spectrum of antibacterial activity, comparable to that of the positive control NQNO.
Subject(s)
Anti-Bacterial Agents , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Staphylococcus aureus/drug effects , Molecular Structure , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Oxides/chemistry , Oxides/pharmacologyABSTRACT
Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f, was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC50 = 91 µM) than CAPA. A different CAPA analogue, 3g, was found to have similar effects against BE(2)-C cells (IC50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells.
Subject(s)
Antineoplastic Agents , Caffeic Acids , Phenylethyl Alcohol , Humans , Caffeic Acids/pharmacology , Caffeic Acids/chemistry , Caffeic Acids/chemical synthesis , HeLa Cells , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Phenylethyl Alcohol/analogs & derivatives , Phenylethyl Alcohol/pharmacology , Phenylethyl Alcohol/chemistry , Phenylethyl Alcohol/chemical synthesis , Water/chemistry , Cell Line, Tumor , Amides/pharmacology , Amides/chemistry , Cell Survival/drug effectsABSTRACT
ProTides are nucleotide analogues used for the treatment of specific viral infections. These compounds consist of a masked nucleotide that undergoes in vivo enzymatic and spontaneous chemical transformations to generate a free mononucleotide that is ultimately transformed to the pharmaceutically active triphosphorylated drug. The three FDA approved ProTides are composed of a phosphoramidate (P-N) core coupled with a nucleoside analogue, phenol, and an l-alanyl carboxylate ester. The previously proposed mechanism of activation postulates the existence of an unstable 5-membered mixed anhydride cyclic intermediate formed from the direct attack of the carboxylate group of the l-alanyl moiety with expulsion of phenol. The mixed anhydride cyclic intermediate is further postulated to undergo spontaneous hydrolysis to form a linear l-alanyl phosphoramidate product. In the proposed mechanism of activation, the 5-membered mixed anhydride intermediate has been detected previously using mass spectrometry, but the specific site of nucleophilic attack by water (P-O versus C-O) has not been determined. To further interrogate the mechanism for hydrolysis of the putative 5-membered cyclic intermediate formed during ProTide activation, the reaction was conducted in 18O-labeled water using a ProTide analogue that could be activated by carboxypeptidase Y. Mass spectrometry and 31P NMR spectroscopy were used to demonstrate that the hydrolysis of the mixed anhydride 5-membered intermediate occurs with exclusive attack at the phosphorus center.
Subject(s)
Phosphoric Acids , Hydrolysis , Phosphoric Acids/chemistry , Phosphoric Acids/metabolism , Amides/chemistry , Amides/metabolism , Stereoisomerism , Oxygen Isotopes/chemistry , Anhydrides/chemistry , Magnetic Resonance Spectroscopy/methods , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Water/chemistry , ProTidesABSTRACT
The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.
Subject(s)
Inflammatory Bowel Diseases , Receptors, Purinergic P2 , Thiophenes , Animals , Thiophenes/pharmacology , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/therapeutic use , Humans , Mice , Inflammatory Bowel Diseases/drug therapy , Receptors, Purinergic P2/metabolism , Structure-Activity Relationship , Purinergic P2 Receptor Antagonists/pharmacology , Purinergic P2 Receptor Antagonists/chemistry , Purinergic P2 Receptor Antagonists/chemical synthesis , Purinergic P2 Receptor Antagonists/therapeutic use , Male , Drug Discovery , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Amides/therapeutic use , Microsomes, Liver/metabolism , Molecular Dynamics Simulation , Colitis/drug therapyABSTRACT
In this study, Density-functional theory/Time-dependent density-functional theory (DFT/TDDFT) and Molecular docking method was used to investigate the effect of methyl acetate, tetrahydrofuran and cyanobenzylidene substituents on the electronic structure and antiviral activity of favipiravir for treating COVID-19. The DFT and TDDFT computations were employed using the Gaussian 09 software package. The values were calculated using the 6-311++G(d, p) basis set and the hybrid B3LYP functional method. Autodock vina software was used for simulations to better predictions and to validate the modified compounds' binding affinities and poses. Results of the study indicate that compounds 1 to 6 all displayed a planar structure, where the pyrazine ring, carboxamide, hydroxyl groups, and other substituents are all situated within the same plane. In addition, the energy gaps (Egap) of these six compounds (Cpd 1, 2, 3, 4, 5, and 6) were compared. The significant dipole moment and binding affinity achieved implies a particular orientation for binding within the target protein, signaling the anticipated strength of the binding interaction. In all six compounds, the electrophilic domain is situated in the vicinity of the amine functional group within the carboxamide compound, whereas the nucleophilic domain encompasses both the carbonyl and hydroxyl groups. The most negatively charged sites are susceptible to electrophilic interactions. In conclusion, compounds 5 and 6 exhibit a high binding affinity of the target protein, while compound 6 has a high energy gap, which could enhance its antiviral activity against the COVID-19 virus.
Subject(s)
Amides , Antiviral Agents , COVID-19 Drug Treatment , Molecular Docking Simulation , Pyrazines , SARS-CoV-2 , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Pyrazines/chemistry , Pyrazines/pharmacology , Amides/chemistry , Amides/pharmacology , SARS-CoV-2/drug effects , Humans , Density Functional Theory , Protein BindingABSTRACT
α-Glucosidase inhibitory activity of galbanic acid and its new amide derivatives 3a-n were investigated. Galbanic acid and compounds 3a-n showed excellent anti-α-glucosidase activity with IC50 values ranging from 0.3 ± 0.3 µM to 416.0 ± 0.2 µM in comparison to positive control acarbose with IC50 value of = 750.0 ± 5.6. In the kinetic study, the most potent compound 3h demonstrated a competitive mode of inhibition with Ki = 0.57 µM. The interaction of the most potent compound 3h with the α-glucosidase was further elaborated by in vitro Circular dichroism assessment and in silico molecular docking and Molecular dynamics studies. Compound 3h was also non-cytotoxic on human normal cells. In silico study on pharmacokinetics and toxicity profile of the most potent galbanic acid derivatives demonstrated that these compounds are valuable lead compounds for further study in order to achieve new anti-diabetic agents.
Subject(s)
Amides , Glycoside Hydrolase Inhibitors , Molecular Docking Simulation , alpha-Glucosidases , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/chemical synthesis , alpha-Glucosidases/metabolism , Humans , Structure-Activity Relationship , Molecular Structure , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Dose-Response Relationship, Drug , Saccharomyces cerevisiae/enzymologyABSTRACT
SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity (KD = 0.29 µM), enzymatic activity (IC50 = 1.2 µM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC50 = 7-24 µM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability (F = 14%) and half-life time (t1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.
Subject(s)
Amides , Antineoplastic Agents , Drug Design , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Animals , Allosteric Regulation/drug effects , Amides/pharmacology , Amides/chemistry , Amides/chemical synthesis , Mice , Cell Line, Tumor , Structure-Activity Relationship , Furans/pharmacology , Furans/chemistry , Furans/chemical synthesis , Xenograft Model Antitumor Assays , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Cell Proliferation/drug effects , Mice, NudeABSTRACT
In our previous study, coumarin-containing CYP51 inhibitor A32 demonstrated potent antiresistance activity. However, compound A32 demonstrated unsatisfied metabolic stability, necessitating modifications to overcome these limitations. In this study, α,ß-unsaturated amides were used to replace the unstable coumarin ring, which increased metabolic stability by four times while maintaining antifungal activity, including activity against resistant strains. Subsequently, the sterol composition analysis and morphological observation experiments indicated that the target of these novel compounds is lanosterol 14α-demethylase (CYP51). Meanwhile, biofilm growth was inhibited and resistance genes (ERG11, CDR1, CDR2, and MDR1) expression was downregulated to find out how the antiresistance works. Importantly, compound C07 demonstrated the capacity to stimulate reactive oxygen species, thus displaying potent fungicidal activity. Moreover, C07 exhibited encouraging effectiveness in vivo following intraperitoneal administration. Additionally, the most potent compound C07 showed satisfactory pharmacokinetic properties and low toxicity. These α,ß-unsaturated amide derivatives, particularly C07, are potential candidates for treating azole-resistant candidiasis.
Subject(s)
Amides , Antifungal Agents , Drug Resistance, Fungal , Microbial Sensitivity Tests , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/chemical synthesis , Drug Resistance, Fungal/drug effects , Amides/pharmacology , Amides/chemistry , Amides/chemical synthesis , Animals , Biofilms/drug effects , Candida albicans/drug effects , Sterol 14-Demethylase/metabolism , Sterol 14-Demethylase/chemistry , Mice , Drug Discovery , Structure-Activity Relationship , Coumarins/pharmacology , Coumarins/chemistry , Coumarins/chemical synthesis , 14-alpha Demethylase Inhibitors/pharmacology , 14-alpha Demethylase Inhibitors/chemistry , 14-alpha Demethylase Inhibitors/chemical synthesis , 14-alpha Demethylase Inhibitors/therapeutic use , Candidiasis/drug therapy , Candidiasis/microbiology , Reactive Oxygen Species/metabolismABSTRACT
Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome ß5 active-site (Pfß5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto ß7. Inhibition of Pfß5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the ß5/ß6/ß3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.
Subject(s)
Antimalarials , Piperidines , Plasmodium falciparum , Proteasome Inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Animals , Antimalarials/pharmacology , Antimalarials/chemistry , Humans , Mice , Proteasome Inhibitors/pharmacology , Proteasome Inhibitors/chemistry , Proteasome Inhibitors/chemical synthesis , Administration, Oral , Proteasome Endopeptidase Complex/metabolism , Malaria/drug therapy , Malaria/parasitology , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Malaria, Falciparum/drug therapy , Female , Molecular StructureABSTRACT
Two new p-cresol-2,6-bis(amide-tether-dpa4-X) ligands (HL4-X, X = MeO and Cl) and their dicopper complexes [Cu2(µ-1,1-OAc)(µ-1,3-OAc)(L4-MeO)]Y (Y = PF6 1a, OAc 1b) and [Cu2(µ-1,3-OAc)2(L4-Cl)]Y (Y = ClO4 2a, OAc 2b) were synthesized. The electronic and hydrophobic effects of the MeO and Cl groups were examined compared with nonsubstituted complex [Cu2(µ-1,1-OAc)(µ-1,3-OAc)(L)]+ (3). The electronic effects were found in crystal structures, spectroscopic characterization, and redox potentials of these complexes. 1b and 2b were reduced to Cu(I)Cu(I) with sodium ascorbate and reductively activated O2 to produce H2O2 and HOâ¢. The H2O2 release and HO⢠generation are promoted by the electronic effects. The hydrophobic effects increased the lipophilicity of 1b and 2b. Cellular ROS generation of 1b, 2b, and 3 was visualized by DCFH-DA. To examine the intracellular behavior, boron dipyrromethene (Bodipy)-modified complexes 4B and 5B corresponding to 1b and 2b were synthesized. These support that 1b and 2b are localized at the ER and Golgi apparatus. The cytotoxicity of 1b and 2b against various cell lines was examined by MTT assay. 1b and 2b were 7- and 41-fold more cytotoxic than 3. 1b generated ROS selectively in cancer cell but 2b nonselectively in cancer and normal cells, causing cancer- and normal-cell-selective cytotoxicity, respectively.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Copper , Hydrophobic and Hydrophilic Interactions , Reactive Oxygen Species , Humans , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Reactive Oxygen Species/metabolism , Copper/chemistry , Copper/pharmacology , Drug Screening Assays, Antitumor , Molecular Structure , Cresols/chemistry , Cresols/pharmacology , Cresols/chemical synthesis , Cell Line, Tumor , Cell Survival/drug effects , Cell Proliferation/drug effects , Electrons , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesisABSTRACT
Amide bonds are one of the most prevalent phenomena in nature and are utilized frequently in drug and material design. However, forming amide bonds is not always efficient or high yielding, particularly when the amine used to conjugate to a carboxylic acid is a weak nucleophile. This limitation precludes many useful amino compounds from participating in conjugation reactions to form amides. A particularly valuable amino compound, which is also a very weak nucleophile, is the amino porphyrin, valued for its role as a photosensitizer, fluorescent agent, catalyst, or, upon metalation, even a very efficient contrast agent for magnetic resonance imaging (MRI). In this work, we propose fast and high-yield coupling of an unreactive amine - the amino porphyrin - to carboxylic acid via isothiocyanate conjugation. Reactions can be achieved in one step at room temperature in one hour, achieving quantitative conversion and near perfect selectivity. Both metalated and unmetalated porphyrin, as well as fluorescein isothiocyanate (FITC), demonstrated efficient conjugation. To illustrate the value of the proposed method, we created a new blood-pool MRI contrast agent that reversibly binds to serum albumin. This new blood-pool agent, known as MITC-Deox (MRI isothiocyanate that links with deoxycholic acid), substantially reduced T1 relaxation times in blood vessels in mice, remained stable for 1 hour, cleared from blood by 24 hours, and was eliminated from the body after 4 days. The proposed method for efficient amide formation is a superior alternative to existing coupling methods, opening a door to novel synthesis of MRI contrast agents and beyond.
Subject(s)
Amides , Contrast Media , Porphyrins , Porphyrins/chemistry , Porphyrins/chemical synthesis , Amides/chemistry , Amides/chemical synthesis , Animals , Mice , Contrast Media/chemistry , Contrast Media/chemical synthesis , Magnetic Resonance Imaging , Molecular Structure , Isothiocyanates/chemistry , Fluorescein-5-isothiocyanate/chemistryABSTRACT
To identify potent inhibitors of the type III secretion system (T3SS) in the foodborne pathogen Pseudomonas aeruginosa, we synthesized 35 thiazole-containing aryl amides by merging salicylic acid with various heterocycles through active splicing. Screening for exoS promoter activity led to the discovery of a highly effective T3SS inhibitor from these 35 compounds. Through subsequent experiments, it was confirmed that compound II-22 specifically targeted the T3SS of P. aeruginosa. Additionally, compound II-22 inhibited the secretion of the effector protein ExoS by modulating the CyaB-cAMP/Vfr-ExsA and ExsCED-ExsA regulatory pathways. Furthermore, compound II-22 suppressed the transcription of genes involved in the needle complex assembly, leading to reduced bacterial virulence. Further validation through inoculation tests using Galleria mellonella larvae demonstrated the strong in vivo efficacy of compound II-22. The study also revealed that compound II-22 enhanced the bactericidal activity of antibiotics, such as CIP (ciprofloxacin) and TOB (tobramycin). These results could help develop novel antimicrobial drugs to reduce bacterial resistance.
Subject(s)
Amides , Anti-Bacterial Agents , Bacterial Proteins , Drug Design , Pseudomonas aeruginosa , Thiazoles , Type III Secretion Systems , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/genetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Type III Secretion Systems/genetics , Type III Secretion Systems/antagonists & inhibitors , Type III Secretion Systems/metabolism , Thiazoles/pharmacology , Thiazoles/chemistry , Thiazoles/chemical synthesis , Amides/pharmacology , Amides/chemistry , Amides/chemical synthesis , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Animals , Microbial Sensitivity Tests , Moths/microbiology , HumansABSTRACT
Bioisosteric silicon replacement has proven to be a valuable strategy in the design of bioactive molecules for crop protection and drug development. Twenty-one novel carboxamides possessing a silicon-containing biphenyl moiety were synthesized and tested for their antifungal activity and succinate dehydrogenase (SDH) enzymatic inhibitory activity. Among these novel succinate dehydrogenase inhibitors (SDHIs), compounds 3a, 3e, 4l, and 4o possessing appropriate clog P and topological polar surface area values showed excellent inhibitory effects against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Fusarium graminearum at 10 mg/L in vitro, and the EC50 values of 4l and 4o were 0.52 and 0.16 mg/L against R. solani and 0.066 and 0.054 mg/L against S. sclerotiorum, respectively, which were superior to those of Boscalid. Moreover, compound 3a demonstrated superior SDH enzymatic inhibitory activity (IC50 = 8.70 mg/L), exhibiting 2.54-fold the potency of Boscalid (IC50 = 22.09 mg/L). Docking results and scanning electron microscope experiments revealed similar mode of action between compound 3a and Boscalid. The new silicon-containing carboxamide 3a is a promising SDHI candidate that deserves further investigation.