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1.
Biological Evaluation of Potent Triclosan‐Derived Inhibitors of the Enoyl–Acyl Carrier Protein Reductase InhA in Drug‐Sensitive and Drug‐Resistant Strains of Mycobacterium tuberculosis 下载免费PDF全文
Dr. Jozef Stec Dr. Catherine Vilchèze Dr. Shichun Lun Dr. Alexander L. Perryman Xin Wang Prof. Joel S. Freundlich Prof. William Bishai Prof. William R. Jacobs Jr. Prof. Alan P. Kozikowski 《ChemMedChem》2014,9(11):2528-2537
New triclosan (TRC) analogues were evaluated for their activity against the enoyl–acyl carrier protein reductase InhA in Mycobacterium tuberculosis (Mtb). TRC is a well‐known inhibitor of InhA, and specific modifications to its positions 5 and 4′ afforded 27 derivatives; of these compounds, seven derivatives showed improved potency over that of TRC. These analogues were active against both drug‐susceptible and drug‐resistant Mtb strains. The most active compound in this series, 4‐(n‐butyl)‐1,2,3‐triazolyl TRC derivative 3 , had an MIC value of 0.6 μg mL?1 (1.5 μM ) against wild‐type Mtb. At a concentration equal to its MIC, this compound inhibited purified InhA by 98 %, and showed an IC50 value of 90 nM . Compound 3 and the 5‐methylisoxazole‐modified TRC 14 were able to inhibit the biosynthesis of mycolic acids. Furthermore, mc24914, an Mtb strain overexpressing inhA, was found to be less susceptible to compounds 3 and 14 , supporting the notion that InhA is the likely molecular target of the TRC derivatives presented herein. 相似文献
2.
Marcel K. W. Mackwitz Eva Hesping Dr. Yevgeniya Antonova-Koch Dr. Daniela Diedrich Dr. Tamirat Gebru Woldearegai Assoc. Prof. Dr. Tina Skinner-Adams Mary Clarke Andrea Schöler Laura Limbach Prof. Dr. Thomas Kurz Prof. Dr. Elizabeth A. Winzeler Dr. Jana Held Prof. Dr. Katherine T. Andrews Prof. Dr. Finn K. Hansen 《ChemMedChem》2019,14(9):912-926
Novel malaria intervention strategies are of great importance, given the development of drug resistance in malaria-endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis, and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by using a one-pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure–activity and structure–toxicity relationships. Most compounds displayed potent activity against asexual blood-stage P. falciparum parasites, with IC50 values in the range of 0.0052–0.25 μm and promising selectivity over mammalian cells (SIPf3D7/HepG2: 170–1483). In addition, several compounds showed encouraging sub-micromolar activity against P. berghei exo-erythrocytic forms (PbEEF). Our study led to the discovery of the hit compound N-(2-(benzylamino)-2-oxoethyl)-N-(4-(hydroxycarbamoyl)benzyl)-4-isopropylbenzamide ( 2 h ) as a potent and parasite-specific dual-stage antiplasmodial HDAC inhibitor (IC50 Pf3D7=0.0052 μm , IC50 PbEEF=0.016 μm ). 相似文献
3.
Dr. Florian C. Schrader Dr. Serghei Glinca Dr. Julia M. Sattler Dr. Hans‐Martin Dahse Gustavo A. Afanador Prof. Dr. Sean T. Prigge Prof. Dr. Michael Lanzer Dr. Ann‐Kristin Mueller Prof. Dr. Gerhard Klebe Prof. Dr. Martin Schlitzer 《ChemMedChem》2013,8(3):442-461
Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood‐ and pre‐erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver‐stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood‐stage parasite growth with IC50 values of 1.7 and 3.0 μM and lead to a more prominent developmental attenuation of liver‐stage parasites than the gold‐standard drug, primaquine. 相似文献
4.
Haynes RK Cheu KW Li KY Tang MM Wong HN Chen MJ Guo ZF Guo ZH Coghi P Monti D 《ChemMedChem》2011,6(9):1603-1615
Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH2 of riboflavin (RF), and FADH2 of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH2, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin‐mediated oxidation of RFH2 generated from N‐benzyl‐1,4‐dihydronicotinamide (BNAH)–RF, or FADH2 generated from NADPH or NADPH–Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor–acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ–MB and CQ–artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP–CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ‐resistance transporter (PfCRT). 相似文献
5.
Jovana Stefanovic Dragica Jakovljevic Gordana Gojgic‐Cvijovic Miodrag Lazic Miroslav Vrvic 《应用聚合物科学杂志》2013,127(6):4736-4743
Nystatin, a polyene tetraene antibiotic widely used in the treatment of mycoses, was coupled with oxidized polysaccharide gum Arabic, by forming Schiff base structures between amine groups of antibiotics and aldehyde groups of modified carbohydrate. Imine conjugates synthesized in this way were reduced with sodium borohydride to secondary amines. Two imine and two amine conjugates were obtained with different nystatin content. The conjugates were characterized by UV–Vis, FTIR, 1H NMR spectroscopy, and thermogravimetric analysis. Solubility in water, unlike nystatin, and significant activity against Candida albicans and Aspergillus niger with minimum inhibitory concentrations in range of 3.125–6.25 μg mL?1 and 6.25–25 μg mL?1, respectively, indicate that the chemical integrity and the biological function of these compounds were retained. A comparison of stability of the conjugates in the dry form, solution and under different pH values showed that the conjugates exhibited better stability than pure drug. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013 相似文献
6.
Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action 下载免费PDF全文
Dr. Christoph Boss Dr. Hamed Aissaoui Nathalie Amaral Aude Bauer Stephanie Bazire Dr. Christoph Binkert Prof. Reto Brun Dr. Cédric Bürki Dr. Claire‐Lise Ciana Dr. Olivier Corminboeuf Stephane Delahaye Claire Dollinger Christoph Fischli Dr. Walter Fischli Alexandre Flock Dr. Marie‐Céline Frantz Malory Girault Dr. Corinna Grisostomi Astrid Friedli Dr. Bibia Heidmann Claire Hinder Gael Jacob Amelie Le Bihan Sophie Malrieu Dr. Saskia Mamzed Aurelien Merot Dr. Solange Meyer Dr. Sabrina Peixoto Nolwenn Petit Dr. Romain Siegrist Julien Trollux Dr. Thomas Weller Dr. Sergio Wittlin 《ChemMedChem》2016,11(18):1995-2014
More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub‐Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine‐based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT‐451840 [(S,E)‐N‐(4‐(4‐acetylpiperazin‐1‐yl)benzyl)‐3‐(4‐(tert‐butyl)phenyl)‐N‐(1‐(4‐(4‐cyanobenzyl)piperazin‐1‐yl)‐1‐oxo‐3‐phenylpropan‐2‐yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy. 相似文献
7.
From Antidiabetic to Antifungal: Discovery of Highly Potent Triazole–Thiazolidinedione Hybrids as Novel Antifungal Agents 下载免费PDF全文
Shanchao Wu Yongqiang Zhang Xiaomeng He Dr. Xiaoying Che Dr. Shengzheng Wang Yang Liu Yan Jiang Na Liu Dr. Guoqiang Dong Prof. Jianzhong Yao Prof. Zhenyuan Miao Prof. Yan Wang Prof. Wannian Zhang Prof. Chunquan Sheng 《ChemMedChem》2014,9(12):2639-2646
In an attempt to discover a new generation of triazole antifungal agents, a series of triazole–thiazolidinedione hybrids were designed and synthesized by molecular hybridization of the antifungal agent fluconazole and rosiglitazone (an antidiabetic). Most of the target compounds showed good to excellent inhibitory activity against a variety of clinically important fungal pathogens. In particular, compounds (Z)‐5‐(2,4‐dichlorobenzylidene)‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)thiazolidine‐2,4‐dione) ( 15 c ), (Z)‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(furan‐3‐ylmethylene)thiazolidine‐2,4‐dione ( 15 j ), and (Z)‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(furan‐3‐ylmethylene)thiazolidine‐2,4‐dione ( 15 r ) were highly active against Candida albicans, with MIC80 values in the range of 0.03–0.15 μM . Moreover, compounds 15 j and 15 r were found to be effective against four fluconazole‐resistant clinical isolates; these two compounds are particularly promising antifungal leads for further optimization. Molecular docking studies revealed that the hydrogen bonding interactions between thiazolidinedione and CYP51 from C. albicans are important for antifungal activity. This study also demonstrates the effectiveness of molecular hybridization in antifungal drug discovery. 相似文献
8.
Despite considerable efforts, malaria remains one of the most devastating infectious disease worldwide. In the absence of an effective vaccine, the prophylaxis and management of Plasmodium infections still rely on the therapeutic use of antimalarial agents. However, the emergence of resistant parasites has jeopardized the efficiency of virtually all antimalarial drugs, including artemisinin combination therapies (ACTs). Thus, there is an urgent need for innovative treatments with novel targets to avoid or overcome drug resistance. In this context, Huang & colleagues prioritized compounds that can block the activity of epigenetic enzymes, and described the discovery of a selective P. falciparum histone deacetylase (HDAC) inhibitor with high activity against various stages of the parasite. These findings may pave the way toward developing new lead compounds with broad-spectrum activity, thus facilitating malaria treatment and elimination. 相似文献
9.
Repurposing the Chemical Scaffold of the Anti‐Arthritic Drug Lobenzarit to Target Tryptophan Biosynthesis in Mycobacterium tuberculosis 下载免费PDF全文
Dr. Genevieve L. Evans Dr. Swarna A. Gamage Dr. Esther M. M. Bulloch Prof. Edward N. Baker Prof. William A. Denny Assoc. Prof. J. Shaun Lott 《Chembiochem : a European journal of chemical biology》2014,15(6):852-864
The emergence of extensively drug‐resistant strains of Mycobacterium tuberculosis (Mtb) highlights the need for new therapeutics to treat tuberculosis. We are attempting to fast‐track a targeted approach to drug design by generating analogues of a validated hit from molecular library screening that shares its chemical scaffold with a current therapeutic, the anti‐arthritic drug Lobenzarit (LBZ). Our target, anthranilate phosphoribosyltransferase (AnPRT), is an enzyme from the tryptophan biosynthetic pathway in Mtb. A bifurcated hydrogen bond was found to be a key feature of the LBZ‐like chemical scaffold and critical for enzyme inhibition. We have determined crystal structures of compounds in complex with the enzyme that indicate that the bifurcated hydrogen bond assists in orientating compounds in the correct conformation to interact with key residues in the substrate‐binding tunnel of Mtb‐AnPRT. Characterising the inhibitory potency of the hit and its analogues in different ways proved useful, due to the multiple substrates and substrate binding sites of this enzyme. Binding in a site other than the catalytic site was found to be associated with partial inhibition. An analogue, 2‐(2‐5‐methylcarboxyphenylamino)‐3‐methylbenzoic acid, that bound at the catalytic site and caused complete, rather than partial, inhibition of enzyme activity was found. Therefore, we designed and synthesised an extended version of the scaffold on the basis of this observation. The resultant compound, 2,6‐bis‐(2‐carboxyphenylamino)benzoate, is a 40‐fold more potent inhibitor of the enzyme than the original hit and provides direction for further structure‐based drug design. 相似文献
10.
Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains 下载免费PDF全文
Dr. Bruno Tasso Dr. Federica Novelli Dr. Michele Tonelli Dr. Anna Barteselli Dr. Nicoletta Basilico Dr. Silvia Parapini Prof. Donatella Taramelli Prof. Anna Sparatore Prof. Fabio Sparatore 《ChemMedChem》2015,10(9):1570-1583
Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria‐related deaths, has developed resistance against this drug. Twenty‐seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro‐2H‐quinolizine and 1,2,3,4,5,6‐hexahydro‐1,5‐methano‐8H‐pyrido[1,2‐a][1,5]diazocin‐8‐one, were synthesized and tested for activity against D‐10 (CQ‐susceptible) and W‐2 (CQ‐resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub‐micromolar IC50 values. Eleven compounds were found to be 2.7‐ to 13.4‐fold more potent than CQ against the W‐2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC‐1 and HepG2) along with easier synthetic accessibility. Replacement of the 4‐NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria. 相似文献
11.
Structure‐Guided Design of Thiazolidine Derivatives as Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors 下载免费PDF全文
Parthiban Brindha Devi Ganesh Samala Jonnalagadda Padma Sridevi Shalini Saxena Mallika Alvala Elena G. Salina Prof. Dharmarajan Sriram Prof. Perumal Yogeeswari 《ChemMedChem》2014,9(11):2538-2547
The pantothenate biosynthetic pathway is essential for the persistent growth and virulence of Mycobacterium tuberculosis (Mtb) and one of the enzymes in the pathway, pantothenate synthetase (PS, EC: 6.3.2.1), encoded by the panC gene, has become an appropriate target for new therapeutics to treat tuberculosis. Herein, we report nanomolar thiazolidine inhibitors of Mtb PS developed by a rational inhibitor design approach. The thiazolidine compounds were discovered by using energy‐based pharmacophore modelling and subsequent in vitro screening, which resulted in compounds with a half maximal inhibitory concentration (IC50) value of (1.12±0.12) μM . These compounds were subsequently optimised by a combination of modelling and synthetic chemistry. Hit expansion of the lead by chemical synthesis led to an improved inhibitor with an IC50 value of 350 nM and an Mtb minimum inhibitory concentration (MIC) of 1.55 μM . Some of these compounds also showed good activity against dormant Mtb cells. 相似文献
12.
Comparative Cytotoxicity of Artemisinin and Cisplatin and Their Interactions with Chlorogenic Acids in MCF7 Breast Cancer Cells 下载免费PDF全文
Dr. John O. Suberu Dr. Isolda Romero‐Canelón Dr. Neil Sullivan Prof. Alexei A. Lapkin Dr. Guy C. Barker 《ChemMedChem》2014,9(12):2791-2797
In parts of Africa and Asia, self‐medication with a hot water infusion of Artemisia annua (Artemisia tea) is a common practice for a number of ailments including malaria and cancer. In our earlier work, such an extract showed better potency than artemisinin alone against both chloroquine‐sensitive and ‐resistant parasites. In this study, in vitro tests of the infusion in MCF7 cells showed high IC50 values (>200 μM ). The combination of artemisinin and 3‐caffeoylquinic acid (3CA), two major components in the extract, was strongly antagonistic and gave a near total loss of cytotoxicity for artemisinin. We observed that the interaction of 3CAs with another cytotoxic compound, cisplatin, showed potentiation of activity by 2.5‐fold. The chelation of cellular iron by 3CA is hypothesized as a possible explanation for the loss of artemisinin activity. 相似文献
13.
Development of Cyclobutene‐ and Cyclobutane‐Functionalized Fatty Acids with Inhibitory Activity against Mycobacterium tuberculosis 下载免费PDF全文
Wantanee Sittiwong Denise K. Zinniel Robert J. Fenton Darrell D. Marshall Courtney B. Story Dr. Bohkyung Kim Prof. Ji‐Young Lee Prof. Robert Powers Prof. Raúl G. Barletta Prof. Patrick H. Dussault 《ChemMedChem》2014,9(8):1838-1849
Eleven fatty acid analogues incorporating four‐membered carbocycles (cyclobutenes, cyclobutanes, cyclobutanones, and cyclobutanols) were investigated for the ability to inhibit the growth of Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb). A number of the analogues displayed inhibitory activity against both mycobacterial species in minimal media. Several of the molecules displayed potent levels of inhibition against Mtb, with MIC values equal to or below those observed with the anti‐tuberculosis drugs D ‐cycloserine and isoniazid. In contrast, two of the analogues that display the greatest activity against Mtb failed to inhibit E. coli growth under either set of conditions. Thus, the active molecules identified herein may provide the basis for the development of anti‐mycobacterial agents against Mtb. 相似文献
14.
Madeline E. Kavanagh Janine L. Gray Sophie H. Gilbert Dr. Anthony G. Coyne Dr. Kirsty J. McLean Holly J. Davis Prof. Andrew W. Munro Prof. Chris Abell 《ChemMedChem》2016,11(17):1924-1935
The cyclo‐dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor‐like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other Mtb P450s. Spectroscopic characterisation of the inhibitors′ binding mode provides insight into the effect of weak nitrogen‐donor ligands on the P450 heme, an improved understanding of factors governing CYP121–ligand recognition and speculation into the biological role of the enzyme for Mtb. 相似文献
15.
Williams CC Thang SH Hantke T Vogel U Seeberger PH Tsanaktsidis J Lepenies B 《ChemMedChem》2012,7(2):281-291
A series of well‐defined polymer–drug conjugates were prepared in order to modify the physical properties of a known cytotoxic drug, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), the active metabolite of irinotecan (CPT‐11). Reversible addition–fragmentation chain transfer (RAFT) polymerisation was used to covalently and site‐specifically append a defined N‐(2‐hydroxypropyl)methacrylamide (HPMA) polymer to SN‐38 using a graft‐from process. These poly‐HPMA–SN‐38 conjugates displayed excellent aqueous solubility and stability, whilst retaining the cytotoxic activity of the parent SN‐38. In vitro co‐culture assays containing both cancer and noncancer cell lines demonstrated the specificity of RAFT‐derived poly‐HPMA–SN‐38 conjugates for cancerous cells. The concept of post‐optimisation modification of small‐molecule drugs through a graft‐from polymer conjugation method is introduced. 相似文献
16.
Aryl Bis‐Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum 下载免费PDF全文
Jonas Thelemann Dr. Boris Illarionov Dr. Konstantin Barylyuk Dr. Julie Geist Prof. Dr. Johannes Kirchmair Dr. Petra Schneider Lucile Anthore Katharina Root Dr. Nils Trapp Prof. Dr. Adelbert Bacher Dr. Matthias Witschel Prof. Dr. Renato Zenobi Prof. Dr. Markus Fischer Prof. Dr. Gisbert Schneider Prof. Dr. François Diederich 《ChemMedChem》2015,10(12):2090-2098
2‐Methylerythritol 2,4‐cyclodiphosphate synthase (IspF) is an essential enzyme for the biosynthesis of isoprenoid precursors in plants and many human pathogens. The protein is an attractive target for the development of anti‐infectives and herbicides. Using a photometric assay, a screen of 40 000 compounds on IspF from Arabidopsis thaliana afforded symmetrical aryl bis‐sulfonamides that inhibit IspF from A. thaliana (AtIspF) and Plasmodium falciparum (PfIspF) with IC50 values in the micromolar range. The ortho‐bis‐sulfonamide structural motif is essential for inhibitory activity. The best derivatives obtained by parallel synthesis showed IC50 values of 1.4 μm against PfIspF and 240 nm against AtIspF. Substantial herbicidal activity was observed at a dose of 2 kg ha?1. Molecular modeling studies served as the basis for an in silico search targeted at the discovery of novel, non‐symmetrical sulfonamide IspF inhibitors. The designed compounds were found to exhibit inhibitory activities in the double‐digit micromolar IC50 range. 相似文献
17.
Synthesis,Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO‐B Inhibitors 下载免费PDF全文
Bijo Mathew Abitha Haridas Prof. Dr. Gülberk Uçar Ipek Baysal Monu Joy Githa E. Mathew Dr. Baskar Lakshmanan Dr. Venkatesan Jayaprakash 《ChemMedChem》2016,11(11):1161-1171
A series of (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(para‐substituted phenyl)prop‐2‐en‐1‐ones ( TB1 – TB11 ) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO‐B except (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( TB7 ) and (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐chlorophenyl)prop‐2‐en‐1‐one ( TB8 ), which were selective inhibitors of hMAO‐A. The most potent compound, (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐[4‐(dimethylamino)phenyl]prop‐2‐en‐1‐one ( TB5 ), showed the best inhibitory activity and higher selectivity toward hMAO‐B, with Ki and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood–brain barrier. Moreover, the most potent MAO‐B inhibitor, TB5 , was found to be nontoxic at 5 and 25 μm , with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency. 相似文献
18.
Time‐Dependent Diaryl Ether Inhibitors of InhA: Structure–Activity Relationship Studies of Enzyme Inhibition,Antibacterial Activity,and in vivo Efficacy 下载免费PDF全文
Dr. Pan Pan Dr. Susan E. Knudson Dr. Gopal R. Bommineni Dr. Huei‐Jiun Li Cheng‐Tsung Lai Dr. Nina Liu Prof. Miguel Garcia‐Diaz Prof. Carlos Simmerling Dr. Sachindra S. Patil Prof. Richard A. Slayden Prof. Peter J. Tonge 《ChemMedChem》2014,9(4):776-791
The diaryl ethers are a novel class of antituberculosis drug candidates that inhibit InhA, the enoyl‐ACP reductase involved in the fatty acid biosynthesis (FASII) pathway, and have antibacterial activity against both drug‐sensitive and drug‐resistant strains of Mycobacterium tuberculosis. In the present work, we demonstrate that two time‐dependent B‐ring modified diaryl ether InhA inhibitors have antibacterial activity in a mouse model of TB infection when delivered by intraperitoneal injection. We propose that the efficacy of these compounds is related to their residence time on the enzyme, and to identify structural features that modulate drug–target residence time in this system, we have explored the inhibition of InhA by a series of B‐ring modified analogues. Seven ortho‐substituted compounds were found to be time‐dependent inhibitors of InhA, where the slow step leading to the final enzyme–inhibitor complex (EI*) is thought to correlate with closure and ordering of the InhA substrate binding loop. A detailed mechanistic understanding of the molecular basis for residence time in this system will facilitate the development of InhA inhibitors with improved in vivo activity. 相似文献
19.
Dr. Anwei Hou Bei Li Prof. Zixin Deng Dr. Min Xu Prof. Dr. Jeroen S. Dickschat 《Chembiochem : a European journal of chemical biology》2023,24(12):e202300154
Cladosporin, a unique natural product from the fungus Cladosporium cladosporioides, exhibits nanomolar inhibitory activity against Plasmodium falciparum by targeting its cytosolic lysyl-tRNA synthetase (PfKRS) to inhibit protein biosynthesis. Due to its exquisite selectivity towards pathogenic parasites, cladosporin has become a very promising lead compound for developing antiparasitic drugs to treat drug-resistant malaria and cryptosporidiosis infections. Here we review the recent research progress of cladosporin covering aspects of the chemical synthesis, biosynthesis, bioactivity, cellular target and structure–activity relationship. 相似文献
20.
Tuberculosis (TB) is a major health problem, with approximately one‐third of the world′s population infected with Mycobacterium tuberculosis, eight million people in the active disease state, and two million dying annually. Furthermore, the prevalence of TB/HIV co‐infection, and the emergence of multidrug‐resistant tuberculosis (MDR‐TB) and extensively drug‐resistant tuberculosis (XDR‐TB) have further aggravated the spread of this disease and thus mortality by it. There is an urgent need for novel antitubercular agents with improved properties, such as lower toxicity, shortened duration of therapy, rapid bactericidal action, and enhanced activity against MDR strains. Fortunately, a number of new potential antitubercular candidate drugs with heterocyclic rings, which are most likely to be effective against resistant strains, have entered clinical trials in recent years. This review highlights recent advances in the research of novel heterocyclic compounds, with particular focus on their antimycobacterial activity, mechanisms of action, toxicity, and structure–activity relationships (SARs). 相似文献