ABSTRACT
The crystal structure of the dopamine D3 receptor (D3R) in complex with eticlopride inspired the design of bitopic ligands that explored (1) N-alkylation of the eticlopride's pyrrolidine ring, (2) shifting of the position of the pyrrolidine nitrogen, (3) expansion of the pyrrolidine ring system, and (4) incorporation of O-alkylations at the 4-position. Structure activity relationships (SAR) revealed that moving the N- or expanding the pyrrolidine ring was detrimental to D2R/D3R binding affinities. Small pyrrolidine N-alkyl groups were poorly tolerated, but the addition of a linker and secondary pharmacophore (SP) improved affinities. Moreover, O-alkylated analogues showed higher binding affinities compared to analogously N-alkylated compounds, e.g., O-alkylated 33 (D3R, 0.436 nM and D2R, 1.77 nM) vs the N-alkylated 11 (D3R, 6.97 nM and D2R, 25.3 nM). All lead molecules were functional D2R/D3R antagonists. Molecular models confirmed that 4-position modifications would be well-tolerated for future D2R/D3R bioconjugate tools that require long linkers and or sterically bulky groups.
Subject(s)
Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Salicylamides/pharmacology , Dose-Response Relationship, Drug , Humans , Ligands , Models, Molecular , Molecular Structure , Salicylamides/chemical synthesis , Salicylamides/chemistry , Structure-Activity RelationshipABSTRACT
The effective treatment of adenovirus (HAdV) infections in immunocompromised patients still poses great challenges. Herein, we reported our continued efforts to optimize a series of salicylamide derivatives as potent inhibitors of HAdV infection. Of these, nine compounds (11, 13, 14, 17, 20, 58, 60, 62, and 70) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC50 values and high selectivity indexes (SI > 100), indicating better safety windows, compared to those of the lead compound niclosamide. Our mechanistic assays suggest that compounds 13, 62, and 70 exert their activities in the HAdV entry pathway, while compounds 14 and 60 likely target the HAdV DNA replication, and 11, 17, 20, and 58 inhibit later steps after DNA replication. Given the broad anti-viral activity profile of niclosamide, these derivatives may also offer therapeutic potential for other viral infections.
Subject(s)
Adenoviruses, Human/drug effects , Antiviral Agents/pharmacology , Salicylamides/pharmacology , A549 Cells , Antiviral Agents/chemical synthesis , Antiviral Agents/toxicity , DNA/metabolism , DNA Replication/drug effects , Humans , Microbial Sensitivity Tests , Molecular Structure , Salicylamides/chemical synthesis , Salicylamides/toxicity , Structure-Activity Relationship , Virus Internalization/drug effectsABSTRACT
Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.
Subject(s)
Antineoplastic Agents/pharmacology , CREB-Binding Protein/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Salicylamides/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , CREB-Binding Protein/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , HL-60 Cells , Humans , Leukemia, Myeloid, Acute/metabolism , Molecular Structure , Salicylamides/chemical synthesis , Salicylamides/chemistry , Structure-Activity RelationshipABSTRACT
As a group of biologically active compounds, polyether antibiotics (ionophores) show a broad spectrum of interesting pharmacological properties, ranging from anti-bacterial to anti-cancer activities. There is increasing evidence that ionophores, including salinomycin (SAL), and their semi-synthetic analogues are promising candidates for the development of drugs against parasitic diseases. Our previous studies have shown that esterification and amidation of the C1 carboxylate moiety of SAL provides compounds with potent activity against Trypanosoma brucei, protozoan parasites responsible for African trypanosomiasis. In this paper, we present the synthetic pathways, crystal structures and anti-trypanosomal activity of C1 esters, amides and hydroxamic acid conjugates of SAL, its C20-oxo and propargylamine analogues as well novel C1/C20 doubly modified derivatives. Evaluation of the trypanocidal and cytotoxic activity using bloodstream forms of T. brucei and human myeloid HL-60â¯cells revealed that the single-modified C20-oxo and propargylamine precursor molecules 10 and 16 were the most anti-trypanosomal and selective compounds with 50% growth inhibition (GI50) values of 0.037 and 0.035⯵M, and selectivity indices of 252 and 300, respectively. Also the salicylhydroxamic acid conjugate of SAL (compound 9) as well as benzhydroxamic acid and salicylhydroxamic acid conjugates of 10 (compounds 11 and 12) showed promising trypanocidal activities with GI50 values between 0.032 and 0.035⯵M but less favorable selectivities. The findings confirm that modification of SAL can result in derivatives with improved trypanocidal activity that might be interesting lead compounds for further anti-trypanosomal drug development.
Subject(s)
Hydroxamic Acids/pharmacology , Salicylamides/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosomiasis, African/drug therapy , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , HL-60 Cells , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests , Salicylamides/chemical synthesis , Salicylamides/chemistry , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Tumor Cells, CulturedABSTRACT
Netherton syndrome (NS) is a rare and debilitating severe autosomal recessive genetic skin disease with high mortality rates particularly in neonates. NS is caused by loss-of-function SPINK5 mutations leading to unregulated kallikrein 5 (KLK5) and kallikrein 7 (KLK7) activity. Furthermore, KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. Identification of potent and selective KLK5 inhibitors would enable further exploration of the disease biology and could ultimately lead to a treatment for NS. This publication describes how fragmentation of known trypsin-like serine protease (TLSP) inhibitors resulted in the identification of a series of phenolic amidine-based KLK5 inhibitors 1. X-ray crystallography was used to find alternatives to the phenol interaction leading to identification of carbonyl analogues such as lactam 13 and benzimidazole 15. These reversible inhibitors, with selectivity over KLK1 (10-100 fold), provided novel starting points for the guided growth towards suitable tool molecules for the exploration of KLK5 biology.
Subject(s)
Benzamidines/chemistry , Kallikreins/antagonists & inhibitors , Serine Proteinase Inhibitors/chemistry , Animals , Benzamidines/chemical synthesis , Benzamidines/metabolism , Catalytic Domain , Drug Design , Kallikreins/metabolism , Netherton Syndrome/drug therapy , Protein Binding , Salicylamides/chemical synthesis , Salicylamides/chemistry , Salicylamides/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/metabolism , Spodoptera/geneticsABSTRACT
A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu2+-induced Aß1-42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC50 value of 10.4⯵M and 15.2⯵M, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+-induced Aß1-42 aggregation inhibitory potency (42.5% and 31.4% at 25.0⯵M, respectively) and moderate disaggregation ability to self- and Cu2+-induced Aß1-42 aggregation fibrils (23.4% and 27.0% at 25⯵M, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment.
Subject(s)
Alzheimer Disease/drug therapy , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antioxidants/pharmacology , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Salicylamides/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antioxidants/chemical synthesis , Antioxidants/chemistry , Blood-Brain Barrier/drug effects , Butyrylcholinesterase/metabolism , Cell Line , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Design , Electrophorus , Mice , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Protein Aggregates/drug effects , Rats , Salicylamides/chemical synthesis , Salicylamides/chemistry , Structure-Activity RelationshipABSTRACT
Three new series of 5-aminosalicylic acid derivatives; series I (14, 16-18), series II (19-30) and series III (31-41) were synthesized as potential dual COX-2/5-LOX inhibitors. Their chemical structures were confirmed using spectroscopic tools including IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity for all target compounds was evaluated in vivo using carrageenan-induced paw edema. Compound 36 showed the highest anti-inflammatory activity (114.12%) relative to reference drug indomethacin at 4â¯h interval. Selected derivatives were evaluated in vitro to inhibit ovine COX-1, human recombinant COX-2 and 5-LOX enzymes. Compounds 34 &35 exhibited significant COX-2 inhibition (IC50â¯=â¯0.10⯵M) with significant COX-2 selectivity indices (SIâ¯=â¯135 & 145 respectively) approximate to celecoxib (IC50â¯=â¯0.049⯵M, SIâ¯=â¯308.16) and exceeding indomethacin (IC50â¯=â¯0.51⯵M, SIâ¯=â¯0.08). Interestingly, all compounds showed superior 5-LOX inhibitory activity about 2-5 times relative to zileuton. Compound 16 was the superlative 5-LOX inhibitor that revealed (IC50â¯=â¯3.41⯵M) relative to zileuton (IC50â¯=â¯15.6⯵M). Compounds 34, 35, 36 and 41 showed significant dual COX-2/5-LOX inhibitions. The gastric ulcerogenic effect of compound 36 was examined on gastric mucosa of albino rats and they showed superior GI safety profile compared with indomethacin. Molecular docking studies of the compounds into the binding sites of COX-1, COX-2 and 5-LOX allowed us to shed light on the binding mode of these novels dual COX and 5-LOX inhibitors.
Subject(s)
Anti-Ulcer Agents/pharmacology , Cyclooxygenase Inhibitors/pharmacology , Lipoxygenase Inhibitors/pharmacology , Molecular Docking Simulation , Salicylamides/pharmacology , Stomach Ulcer/drug therapy , Animals , Anti-Ulcer Agents/chemical synthesis , Anti-Ulcer Agents/chemistry , Arachidonate 5-Lipoxygenase/metabolism , Carrageenan , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/chemistry , Edema/chemically induced , Edema/drug therapy , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Male , Rats , Rats, Wistar , Salicylamides/chemical synthesis , Salicylamides/chemistry , Stomach Ulcer/chemically inducedABSTRACT
Inhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells. Proteolytic degradation in cells is mainly ensured by proteasome and its inhibition by bortezomib showed benefit in clinical use for the treatment of multiple myeloma. We report here the library of antiproteasomal O-benzyl salicylamides built from leucine and phenylalanine. Prepared compounds displayed antiproliferative activity on K562, CEM and U266 cancer cell lines, ranging from high micromolar to submicromolar GI50 values. The most potent compounds (series 4 and 6) were further assayed for their inhibition of chymotrypsin-like protease activity of the 26S proteasome in U266 cells. The majority of compounds inhibited the proteasome in mid-nanomolar concentrations (IC50 ranging from 57 to 197 nM) and it correlated with cellular potency. In a cell based assay involving green fluorescence protein (GFP) fused to a short degron that is rapidly degraded by a proteasome the compounds induced accumulation of GFP, visualised and quantified by live-cell imaging. Levels of polyubiquitinated proteins in U266 cells treated by compound 4m were also analyzed by immunoblotting, revealing a typical high molecular mass smear of ubiquitin conjugates. Finally, apoptotic cell death in treated U266 cells was detected biochemically by measuring the activity of caspases 3 and 7 in lysates and by immunoblotting of caspase 7, its substrate poly(ADP-ribose)polymerase, and Mcl-1, which all together showed changes typical for apoptosis. All these observations were in agreement with expected cellular mechanism of action and confirmed proteasome targeting by prepared O-benzyl salicylamides.
Subject(s)
Antineoplastic Agents/pharmacology , Leucine/pharmacology , Phenylalanine/pharmacology , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/pharmacology , Salicylamides/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Leucine/chemistry , Molecular Structure , Phenylalanine/chemistry , Proteasome Inhibitors/chemical synthesis , Proteasome Inhibitors/chemistry , Salicylamides/chemical synthesis , Salicylamides/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel salicyl-hydrazone analogues were synthesized and evaluated for their in vitro cytotoxic activities in five human cancer cell lines, namely, lung cancer (A549), ovarian cancer (SK-OV-3), skin cancer (SK-MEL-2), colon cancer (HCT15) and pancreatic cancer (MIA-PaCa-2) cells, and for their in vitro tropomyosin receptor kinase A (TrkA) inhibitory activities. Each of the compounds showed significant cytotoxicity against all cancer cells. Compound 3i was found to be most potent against all cancer cell lines with IC50 values of 2.46 (A549), 0.87 (SK-OV-3), 1.43 (SK-MEL-2), 0.89 (HCT15), and 0.48µM (MIA-PaCa-2), followed by compound 3l. Cytotoxicity of 3i was similar to that of doxorubicin (0.87µM) against HCT15 cells. Compounds 3i and 3l also showed highest TrkA inhibitory activities with IC50 values of 0.231 and 0.380µM, respectively. A SAR study of the series revealed that compounds with hydroxyl groups showed better cytotoxicity and TrkA inhibitory potency (in the following order 2,4-OH>2,3,4-OH>3,4-OH>4-OH) than compounds possessing electron donating or withdrawing groups on the benzylidenephenyl ring. Docking studies of compounds 3i and 3l conducted on the crystal structure of TrkA receptor (a promising target for anticancer agents) showed both had a high docking score and similar order of experimental TrkA inhibitory activities. The formation of several hydrogen bonds involving N and O containing moieties contributed most significantly to ligand binding and stabilization at the active site of the receptor. In addition, ligand-receptor complexes were further stabilized by π-cation, π-anion, amide-π stacked, and van der Waal's interactions. Conformational analyses showed ligand molecules adopted similar conformations at the receptor active site during interactions, but that the low energy optimized conformations of compounds 3i and 3l differed.
Subject(s)
Antineoplastic Agents/pharmacology , Hydrazones/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor, trkA/antagonists & inhibitors , Salicylamides/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Catalytic Domain , Cell Line, Tumor , Doxorubicin/pharmacology , Humans , Hydrazones/chemical synthesis , Hydrazones/chemistry , Hydrogen Bonding , Molecular Conformation , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Salicylamides/chemical synthesis , Salicylamides/chemistry , Structure-Activity RelationshipABSTRACT
(-)-Dehydroxymethylepoxyquinomicin ((-)-DHMEQ, 1) is a specific inhibitor of NF-κB. It binds to SH group in the specific cysteine residue of NF-κB components with its epoxide moiety to inhibit DNA binding. In the present research, we have designed and synthesized an epoxide-free analog called (S)-ß-salicyloylamino-α-exo-methylene-Æ´-butyrolactone (SEMBL, 3). SEMBL inhibited DNA binding of NF-κB component p65 in vitro. It inhibited LPS-induced NF-κB activation, iNOS expression, and inflammatory cytokine secretions. It also inhibited NF-κB and cellular invasion in ovarian carcinoma ES-2 cells. Moreover, its stability in aqueous solution was greatly enhanced compared with (-)-DHMEQ. Thus, SEMBL has a potential to be a candidate for a new anti-inflammatory and anticancer agent.
Subject(s)
4-Butyrolactone/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Drug Design , NF-kappa B/antagonists & inhibitors , Salicylamides/pharmacology , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Mice , Molecular Structure , NF-kappa B/metabolism , RAW 264.7 Cells , Salicylamides/chemical synthesis , Salicylamides/chemistry , Structure-Activity RelationshipABSTRACT
The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700-fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development.
Subject(s)
Dopamine Antagonists/pharmacology , Opioid-Related Disorders/drug therapy , Receptors, Dopamine D3/agonists , Receptors, Dopamine D3/antagonists & inhibitors , Salicylamides/pharmacology , Animals , Behavior, Animal/drug effects , Conditioning, Psychological/drug effects , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Locomotion/drug effects , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Oxycodone , Rats , Rats, Long-Evans , Salicylamides/chemical synthesis , Salicylamides/chemistry , Structure-Activity RelationshipABSTRACT
Promysalin is a species-specific Pseudomonad metabolite with unique bioactivity. To better understand the mode of action of this natural product, we synthesized 16 analogs utilizing diverted total synthesis (DTS). Our analog studies revealed that the bioactivity of promysalin is sensitive to changes within its hydrogen bond network whereby alteration has drastic biological consequences. The DTS library not only yielded three analogs that retained potency but also provided insights that resulted in the identification of a previously unknown ability of promysalin to bind iron. These findings coupled with previous observations hint at a complex multifaceted role of the natural product within the rhizosphere.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Iron/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Salicylamides/chemical synthesis , Salicylamides/pharmacology , Anti-Bacterial Agents/chemistry , Biological Products , Hydrogen Bonding , Molecular Conformation , Pseudomonas/drug effects , Pseudomonas/metabolism , Pyrrolidines/chemistry , Salicylamides/chemistry , Siderophores/chemistry , Structure-Activity RelationshipABSTRACT
Acylhydrazones are very versatile ligands and their coordination properties can be easily tuned, giving rise to metal complexes with different nuclearities. In the last few years, we have been looking for new pharmacophores able to coordinate simultaneously two metal ions, because many enzymes have two metal ions in the active site and their coordination can be a successful strategy to inhibit the activity of the metalloenzyme. As a part of this ongoing research, we synthesized the acylhydrazone H2L and its complexes with Mg(II), Mn(II), Co(II), Ni(II), Cu(II) and Zn(II). Their characterization, both in solution--also by means of potentiometric studies--and in the solid state, evidenced the ability of the o-vanillin hydrazone scaffold to give rise to different types of metal complexes, depending on the metal and the reaction conditions. Furthermore, we evaluated both the free ligand and its metal complexes in in vitro studies against a panel of diverse DNA- and RNA-viruses. In particular, the Mg(II), Mn(II), Ni(II) and Zn(II) complexes had EC50 values in the low micromolar range, with a pronounced activity against vaccinia virus.
Subject(s)
Antiviral Agents/pharmacology , Chelating Agents/pharmacology , Coordination Complexes/pharmacology , Hydrazones/pharmacology , Salicylamides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Chelating Agents/chemical synthesis , Chelating Agents/chemistry , Chlorocebus aethiops , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Crystallography, X-Ray , DNA Viruses/drug effects , Dogs , HeLa Cells , Humans , Hydrazones/chemical synthesis , Hydrazones/chemistry , Ligands , Magnesium/chemistry , Metals, Heavy/chemistry , Potentiometry , RNA Viruses/drug effects , Salicylamides/chemical synthesis , Salicylamides/chemistry , Vero CellsABSTRACT
Compounds that specifically target pathogenic bacteria are greatly needed, and identifying the method by which they act would provide new avenues of treatment. Herein we report the concise, high-yielding total synthesis (eight steps, 35% yield) of promysalin, a natural product that displays antivirulence phenotypes against pathogenic bacteria. Guided by bioinformatics, four diastereomers were synthesized, and the relative and absolute stereochemistries were confirmed by spectral and biological analysis. Finally, we show for the first time that promysalin displays two antivirulence phenotypes: the dispersion of mature biofilms and the inhibition of pyoverdine production, hinting at a unique pathogenic-specific mechanism of action.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Pseudomonas fluorescens/drug effects , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Salicylamides/chemical synthesis , Salicylamides/pharmacology , Anti-Bacterial Agents/chemistry , Computational Biology , Microbial Sensitivity Tests , Molecular Structure , Oligopeptides/antagonists & inhibitors , Oligopeptides/biosynthesis , Pyrrolidines/chemistry , Salicylamides/chemistryABSTRACT
A novel class of experimental fungicides has been discovered, which consists of special N-thiazol-4-yl-salicylamides. They originated from amide reversion of lead structures from the patent literature and are highly active against important phytopathogens, such as Phytophthora infestans (potato and tomato late blight), Plasmopara viticola (grapevine downy mildew) and Pythium ultimum (damping-off disease). Structure-activity relationship studies revealed the importance of a phenolic or enolic hydroxy function in the ß-position of a carboxamide. An efficient synthesis route has been worked out, which for the first time employs the carbonyldiimidazole-mediated Lossen rearrangement in the field of thiazole carboxylic acids.
Subject(s)
Fungicides, Industrial/chemical synthesis , Fungicides, Industrial/pharmacology , Oomycetes/drug effects , Salicylamides/chemical synthesis , Salicylamides/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Dose-Response Relationship, Drug , Fungicides, Industrial/chemistry , Microbial Sensitivity Tests , Molecular Structure , Salicylamides/chemistry , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
3-Aminomethylation of salicylalkylamides afforded hybrids with a Mannich base. In addition, it triggered the rotation of the amide bond. The observed conformational switch is driven by strong intramolecular hydrogen bonding between the Mannich base and phenolic group. Crystal structure analysis reveals the stabilization of the hybrid molecules by double hydrogen bonding of the phenolic OH, which acts as an acceptor and donor simultaneously. The molecules contain an amide site and a Mannich base site in an orthogonal spatial arrangement. The intramolecular hydrogen bonds are persistent in a nonpolar solvent (e.g., chloroform). The conformational change can be reversed upon protection or protonation of the Mannich base nitrogen.
Subject(s)
Amides/chemistry , Mannich Bases/chemistry , Salicylamides/chemistry , Carbon-13 Magnetic Resonance Spectroscopy , Crystallography, X-Ray , Hydrogen Bonding , Isomerism , Molecular Conformation , Proton Magnetic Resonance Spectroscopy , Salicylamides/chemical synthesis , SolutionsABSTRACT
Inhibition of photosynthetic electron transport (PET) in spinach chloroplasts by sixty-one ring-substituted N-benzylsalicylamides was investigated. The inhibitory potency of the compounds expressed by IC50 value varied from 2.0 to 425.3 µmol/L. Several evaluated compounds can be considered as effective PET inhibitors; these include N-(3,4- dichlorobenzyl)-2-hydroxy-5-nitrobenzamide (IC50 = 2.0 µmol/L), 3,5-dibromo-N-(3,4-dichlorobenzyl)-2-hydroxybenzamide (IC50 = 2.3 µmol/L) and 3,5-dibromo-N-(4-chlorobenzyl)-2-hydroxybenzamide (IC50 = 2.6 µmol/L) with activity comparable with that of the standard Diuron (IC50 = 1.9 µmol/L). The PET inhibiting activity increased approximately linearly with increasing lipophilicity of the compounds as well as with the increasing sum of Hammett σ constants of the substituents on the acyl fragment (R(1) = H, 5-OCH3, 5-CH3, 5-Cl, 5-Br, 5-NO2, 4-OCH3, 4-Cl, 3,5-Cl and 3,5-Br) and the benzylamide fragment (R(2) = H, 4-OCH3, 4-CH3, 4-F, 4-Cl and 3,4-Cl). Based on the evaluated structure-PET inhibiting activity relationships (QSAR) it was confirmed that the inhibitory activity of the compounds depends on lipophilicity (log P or distributive parameters π; (1) and π(2)of individual substituents) and electronic properties of the substituents on the acyl (σ(1)) and the benzylamide fragments (σ(2)), the contribution of σ(1) being more significant than that of σ(2).
Subject(s)
Chloroplasts/drug effects , Photosynthesis/drug effects , Salicylamides/chemical synthesis , Spinacia oleracea/drug effects , Chloroplasts/metabolism , Drug Design , Electron Transport/drug effects , Models, Chemical , Molecular Structure , Quantitative Structure-Activity Relationship , Salicylamides/chemistry , Salicylamides/pharmacology , Spinacia oleracea/metabolismABSTRACT
A series of 1,2,3-triazolylsalicylamide derivatives has been developed from the antiproliferative agent 7 and was evaluated for their Aurora kinase inhibitory activity. The novel 1,2,3-triazolylsalicylamide scaffold could be readily assembled by Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition, allowing rapid access to the structurally diverse analogues. The synthesized 1,2,3-triazolylsalicylamide derivatives revealed a significant Aurora kinase inhibitory activity. In particular, 8g inhibited Aurora A with IC50 values of 0.37µM. The critical role of phenolic -OH in the binding was confirmed by a molecular modeling study.
Subject(s)
Aurora Kinase A/antagonists & inhibitors , Aurora Kinase B/antagonists & inhibitors , Click Chemistry , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Salicylamides/pharmacology , Triazoles/pharmacology , Aurora Kinase A/metabolism , Aurora Kinase B/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Salicylamides/chemical synthesis , Salicylamides/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Three series of salicylanilides, esters of N-phenylsalicylamides and 2-hydroxy-N-[1-(2-hydroxyphenylamino)-1-oxoalkan-2-yl]benzamides, in total thirty target compounds were synthesized and characterized. The compounds were evaluated against seven bacterial and three mycobacterial strains. The antimicrobial activities of some compounds were comparable or higher than the standards ampicillin, ciprofloxacin or isoniazid. Derivatives 3f demonstrated high biological activity against Staphylococcus aureus (⩽0.03µmol/L), Mycobacterium marinum (⩽0.40µmol/L) and Mycobacterium kansasii (1.58µmol/L), 3g shows activity against Clostridium perfringens (⩽0.03µmol/L) and Bacillus cereus (0.09µmol/L), 3h against Pasteurella multocida (⩽0.03µmol/L) and M. kansasii (⩽0.43µmol/L), 3i against methicillin-resistant S. aureus and B. cereus (⩽0.03µmol/L). The structure-activity relationships are discussed for all the compounds.
Subject(s)
Anti-Infective Agents/chemistry , Salicylamides/chemistry , Ampicillin/pharmacology , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Ciprofloxacin/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Salicylamides/chemical synthesis , Salicylamides/pharmacology , Structure-Activity RelationshipABSTRACT
A novel series of N-aryl salicylamides with a hydroxamic acid moiety at 5-position were synthesized efficiently. Their activities against EGFR kinase and HDACs were evaluated. All compounds displayed inhibitory activity against EGFR and HDACs. The antiproliferative activities of synthesized compounds were evaluated by MTT method against human cancer cell lines A431, A549 and HL-60. Compound 1o showed the most potent inhibitory activity against A431 and A549. Compounds 1k and 1n exhibited higher potency against HL-60 than gefitinib and SAHA. N-Aryl salicylamides with a hydroxamic acid moiety at 5-position is another new HDAC-EGFR dual inhibitors.