Design,Synthesis, and in vitro Biological Evaluation of 3,5‐Dimethylisoxazole Derivatives as BRD4 Inhibitors

BRD4 has been identified as a potential target for blocking proliferation in a variety of cancer cell lines. In this study, 3,5‐dimethylisoxazole derivatives were designed and synthesized with excellent stability in liver microsomes as potent BRD4 inhibitors, and were evaluated for their BRD4 inhibitory activities in vitro. Gratifyingly, compound 11 h [3‐((1‐(2,4‐difluorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)‐6‐(3,5‐dimethylisoxazol‐4‐yl)‐4‐phenyl‐3,4‐dihydroquinazolin‐2(1H)‐one] exhibited robust potency for BRD4(1) and BRD4(2) inhibition with IC₅₀ values of 27.0 and 180 nm , respectively. Docking studies were performed to illustrate the strategy of modification and analyze the conformation in detail. Furthermore, compound 11 h was found to potently inhibit cell proliferation in the BRD4‐sensitive cell lines HL‐60 and MV4‐11, with IC₅₀ values of 0.120 and 0.09 μm , respectively. Compound 11 h was further demonstrated to downregulate c‐Myc levels in HL‐60 cells. In summary, these results suggest that compound 11 h is most likely a potential BRD4 inhibitor and is a lead compound for further investigations.     

Coumarin-Thiourea Hybrids Show Potent Carbonic Anhydrase IX and XIII Inhibitory Action

A series of coumarin-thiourea hybrids ( 4 a – o ) has been synthesized, and the compounds have been evaluated against the tumour associated transmembrane isoform, human (h) carbonic anhydrase (CA) hCA IX and the less-explored cytosolic isoform, hCA XIII. All compounds exhibited potent inhibition of both isoforms, with K_I values of <100 nM against hCA IX. Compound 4 b was the best inhibitor (K_I=78.5 nM). All the compounds inhibited hCA XIII in the low-nanomolar to sub-micromolar range, with compound 4 b again showing the best inhibition (K_I=76.3 nM). With compound 4 b as a lead, more-selective inhibitors of hCA IX and hCA XIII or dual hCA IX/XIII inhibitors might be developed.     

Enzymatic Cascade in Pseudomonas that Produces Pyrazine from α-Amino Acids

Pyrazines are widespread chemical compounds that include pheromones and odors. Herein, a novel mechanism used by Pseudomonas fluorescens SBW25 to biosynthesize monocyclic pyrazines is reported. Heterologous expression of the papABC genes that synthesize the natural α-amino acid 4-aminophenylalanine (4APhe), together with three adjacent papDEF genes of unknown function, in Escherichia coli resulted in the production of 2,5-dimethyl-3,6-bis(4-aminobenzyl)pyrazine (DMBAP), which comprised two symmetrical aminobenzyl moieties derived from 4APhe. It is found that PapD is a novel amino acid C-acetyltransferase, which decarboxylates and transfers acetyl residues to 4APhe, to generate an α-aminoketone, which spontaneously dehydrates and condenses to give dihydro DMBAP. PapF is a novel oxidase in the amine oxidase superfamily that oxidizes dihydro DMBAP to yield the pyrazine ring of DMBAP. These two enzymes constitute a unique mechanism for synthesizing monocyclic pyrazines and might serve as a novel strategy for the enzymatic synthesis of pyrazine derivatives from natural α-amino acids.     

4-Sulfamoylphenylalkylamides as Inhibitors of Carbonic Anhydrases Expressed in Vibrio cholerae

A current issue of antimicrobial therapy is the resistance to treatment with worldwide consequences. Thus, the identification of innovative targets is an intriguing challenge in the drug and development process aimed at newer antimicrobial agents. The state-of-art of anticholera therapy might comprise the reduction of the expression of cholera toxin, which could be reached through the inhibition of carbonic anhydrases expressed in Vibrio cholerae (VchCAα, VchCAβ, and VchCAγ). Therefore, we focused our interest on the exploitation of sulfonamides as VchCA inhibitors. We planned to design and synthesize new benzenesulfonamides based on our knowledge of the VchCA catalytic site. The synthesized compounds were tested thus collecting useful SAR information. From our investigation, we identified new potent VchCA inhibitors, some of them displayed high affinity toward VchCAγ class, for which few inhibitors are currently reported in literature. The best interesting VchCAγ inhibitor (S)-N-(1-oxo-1-((4-sulfamoylbenzyl)amino)propan-2-yl)furan-2-carboxamide ( 40 ) resulted more active and selective inhibitor when compared with acetazolamide (AAZ) as well as previously reported VchCA inhibitors.     

Rational Design,Synthesis, and Potency of N‐Substituted Indoles,Pyrroles, and Triarylpyrazoles as Potential Fructose 1,6‐Bisphosphatase Inhibitors

By using computer modeling and lead structures from our earlier SAR results, a broad variety of pyrrole‐, indole‐, and pyrazole‐based compounds were evaluated as potential fructose 1,6‐bisphosphatase (FBPase) inhibitors. The docking studies yielded promising structures, and several were selected for synthesis and FBPase inhibition assays: 1‐[4‐(trifluoromethyl)benzoyl]‐1H‐indole‐5‐carboxamide, 1‐(α‐naphthalen‐1‐ylsulfonyl)‐7‐nitro‐1H‐indole, 5‐(4‐carboxyphenyl)‐3‐phenyl‐1‐[3‐(trifluoromethyl)phenyl]‐1H‐pyrazole, 1‐(4‐carboxyphenylsulfonyl)‐1H‐pyrrole, and 1‐(4‐carbomethoxyphenylsulfonyl)‐1H‐pyrrole were synthesized and tested for inhibition of FBPase. The IC₅₀ values were determined to be 0.991 and 1.34 μM , and 575, 135, and 32 nM , respectively. The tested compounds were significantly more potent than the natural inhibitor AMP (4.0 μM ) by an order of magnitude; indeed, the best inhibitor showed an IC₅₀ value toward FBPase more than two orders of magnitude better than that of AMP. This level of activity is virtually the same as that of the best currently known FBPase inhibitors. This work shows that such indole derivatives are promising candidates for drug development in the treatment of type II diabetes.     

Thiazoles as corrosion inhibitors for mild steel in formic and acetic acid solutions

2-(N,N-dimethylamino) benzylidene imino-4-(4-methyl phenyl)-1,3-thiazole (DIMPT), 2-benzylidene imino-4-(4-methyl phenyl)-1,3-thiazole (BIMPT), 2-salicylidene imino-4-(4-methyl phenyl)-1,3-thiazole (SIMPT) and 2-cinnamylidene imino-4-(4-methyl phenyl)-1,3-thiazole (CIMPT) were synthesized in the laboratory and their influence on the inhibition of corrosion of mild steel in 20 formic acid and 20 acetic acid was investigated by weight loss and potentiodynamic polarization techniques. The inhibition efficiency of these compounds was found to vary with their nature and concentration, temperature, immersion time and acid concentration. The values of activation energy and free energy of adsorption of the thiazoles were calculated to investigate the mechanism of corrosion inhibition. The adsorption of all the thiazoles on mild steel surface was found to obey Langmuir adsorption isotherm. The potentiodynamic polarization result revealed that the compounds studied are mixed type inhibitors. Electrochemical impedance spectroscopy was used to investigate the mechanism of corrosion inhibition.     

Electrochemical and theoretical studies of thienyl-substituted amino triazoles on corrosion inhibition of copper in 0.5 M H<Subscript>2</Subscript>SO<Subscript>4</Subscript>

2,5-Bis(2-thienyl)-4-amino-1,2,4-triazole (2-TAT) and 2,5-bis(3-thienyl)-4-amino-1,2,4-triazole (3-TAT) have been studied as inhibitors for the corrosion of copper in 0.5 M H₂SO₄ using potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). The inhibition efficiency of the triazole compounds increases with increasing concentration, and the effect of 3-TAT is better than that of 2-TAT with the same concentration. Potentiodynamic polarization measurements indicate the triazole compounds act as mixed type inhibitors in 0.5 M H₂SO₄. The adsorption of the triazole compounds is found to obey the Langmuir adsorption isotherm. High significant correlations for the triazole compounds are obtained between inhibition efficiency and quantum chemical parameters (R = 0.975) using the quantitative structure–activity relationship (QSAR) method.     

Corrosion inhibition of mild steel in acidic medium using hydrazide derivatives

The corrosion inhibition characteristics of N′-[(1E)-(4-hydroxy phenyl) methylene] isonicotinohydrazide (HIH) & N′-[(1E)-(4-hydroxyl-3-methoxy phenyl) methylene] isonicotinohydrazide (HMIH) on mild steel corrosion in 1 M hydrochloric acid were investigated by weight loss, potentiodynamic polarization and impedance techniques. The inhibition efficiency increased with increase in inhibitor concentration but decreased with increase in temperature. The thermodynamic functions of dissolution and adsorption processes were evaluated. The polarization measurements indicated that the inhibitors are of mixed type. The adsorption of the compounds was found to obey Langmuir’s adsorption isotherm. Passive film characterization was done by Fourier transform infrared (FTIR) spectra and scanning electron microscopy (SEM).     

1,2,4-Triazole-3-Thione Analogues with a 2-Ethylbenzoic Acid at Position 4 as VIM-type Metallo-β-Lactamase Inhibitors

Metallo-β-lactamases (MBLs) are increasingly involved as a major mechanism of resistance to carbapenems in relevant opportunistic Gram-negative pathogens. Unfortunately, clinically efficient MBL inhibitors still represent an unmet medical need. We previously reported several series of compounds based on the 1,2,4-triazole-3-thione scaffold. In particular, Schiff bases formed between diversely 5-substituted-4-amino compounds and 2-carboxybenzaldehyde were broad-spectrum inhibitors of VIM-type, NDM-1 and IMP-1 MBLs. Unfortunately, these compounds were unable to restore antibiotic susceptibility of MBL-producing bacteria, probably because of poor penetration and/or susceptibility to hydrolysis. To improve their microbiological activity, we synthesized and characterized compounds where the hydrazone-like bond of the Schiff base analogues was replaced by a stable ethyl link. This small change resulted in a narrower inhibition spectrum, as all compounds were poorly or not inhibiting NDM-1 and IMP-1, but showed a significantly better activity on VIM-type enzymes, with K_i values in the μM to sub-μM range. The resolution of the crystallographic structure of VIM-2 in complex with one of the best inhibitors yielded valuable information about their binding mode. Interestingly, several compounds were shown to restore the β-lactam susceptibility of VIM-type-producing E. coli laboratory strains and also of K. pneumoniae clinical isolates. In addition, selected compounds were found to be devoid of toxicity toward human cancer cells at high concentration, thus showing promising safety.     

A Multi-step Virtual Screening Protocol for the Identification of Novel Non-acidic Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) Inhibitors

Microsomal prostaglandin E₂ synthase-1 (mPGES-1) is a potential therapeutic target for the treatment of inflammatory diseases and certain types of cancer. To identify novel scaffolds for mPGES-1 inhibition, we applied a virtual screening (VS) protocol that comprises molecular docking, fingerprints-based clustering with diversity-based selection, protein–ligand interactions fingerprints, and molecular dynamics (MD) simulations with molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The hits identified were carefully analyzed to ensure the selection of novel scaffolds that establish stable interactions with key residues in the mPGES-1 binding pocket and inhibit the catalytic activity of the enzyme. As a result, we discovered two promising chemotypes, 4-(2-chlorophenyl)-N-[(2-{[(propan-2-yl)sulfamoyl]methyl}phenyl)methyl]piperazine-1-carboxamide ( 6 ) and N-(4-methoxy-3-{[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]sulfamoyl}phenyl)acetamide ( 8 ), as non-acidic mPGES-1 inhibitors with IC₅₀ values of 1.2 and 1.3 μm , respectively. Minimal structural optimization of 8 resulted in three more compounds with promising improvements in inhibitory activity (IC₅₀: 0.3–0.6 μm ). The unprecedented chemical structures of 6 and 8 , which are amenable to further derivatization, reveal a new and attractive approach for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties.     

Fatty acid oxadiazoles as corrosion inhibitors for mild steel in formic acid

Selected oxadiazoles of fatty acids; namely 2-hepta decene-5-mercapto-1-oxa-3,4-diazole (HMOD); 2-undecane-5-mercapto-1-oxa-3,4-diazole (UMOD); and 2-decene-5-mercapto-1-oxa-3,4-diazole (DMOD), were synthesized. Their influence on the inhibition of corrosion of mild steel in 20% formic acid (HCOOH) was investigated by weight loss and potentiodynamic polarization techniques. The inhibition efficiency of the compounds was found to vary with concentration, immersion time and temperature. All the compounds showed good inhibition efficiency (e _IE) in formic acid solution. Adsorption on mild steel obeyed the Langmuir adsorption isotherm. Potentiodynamic polarization revealed that all three inhibitors, HMOD, UMOD, and DMOD are mixed inhibitors. Electrochemical impedance spectroscopy was also used to investigate the inhibition mechanism.     

2-Phenyloxazole-4-carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B

A series of 2-phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO-B isoform. The most potent and selective derivatives are characterized by inhibition constant (K_i) values in the sub-micromolar range and a good selectivity index (K_{i MAO-A}/K_{i MAO-B}>50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)-differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2-(2-hydroxyphenyl)-N-phenyloxazole-4-carboxamide (compound 4 a ) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF-differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity.     

Role of some thiadiazole derivatives as inhibitors for the corrosion of C-steel in 1 M H<Subscript>2</Subscript>SO<Subscript>4</Subscript>

Inhibition of C-steel corrosion by some thiadiazole derivatives (I–VI) in 1 M H₂SO₄ was investigated by weight loss, potentiodynamic polarization, linear polarization resistance (LPR) and electrochemical impedance spectroscopy (EIS) techniques. The presence of these compounds in the solution decreases the double layer capacitance, increases the charge transfer resistance and increase of linear polarization. Polarization studies were carried out at room temperature, and showed that all the compounds studied are mixed type inhibitors with a slight predominance of cathodic character. The effect of temperature on corrosion inhibition has been studied and the thermodynamic activation and adsorption parameters were calculated and discussed. Electrochemical impedance was used to investigate the mechanism of corrosion inhibition. The adsorption of the compounds on C-steel was found to obey Langmuir’s adsorption isotherm. The synergistic effect brought about by combination of the inhibitors and KSCN, KI and KBr was examined and explained. The mechanism of inhibition process was discussed in the light of the chemical structure and quantum-chemical calculations of the investigated inhibitors.     

Development of Novel Amides as Noncovalent Inhibitors of Immunoproteasomes

The development of immunoproteasome-selective inhibitors is a promising strategy for treating hematologic malignancies, autoimmune and inflammatory diseases. In this context, we report the design, synthesis, and biological evaluation of a new series of amide derivatives as immunoproteasome inhibitors. Notably, the designed compounds act as noncovalent inhibitors, which might be a promising therapeutic option because of the lack of drawbacks and side effects associated with irreversible inhibition. Among the synthesized compounds, we identified a panel of active inhibitors with K_i values in the low micromolar or sub-micromolar ranges toward the β5i and/or β1i subunits of immunoproteasomes. One of the active compounds was shown to be the most potent and selective inhibitor with a K_i value of 21 nm against the single β1i subunit. Docking studies allowed us to determine the mode of binding of the molecules in the catalytic site of immunoproteasome subunits.     

Some new triazole derivatives as inhibitors for mild steel corrosion in acidic medium

Two triazole derivatives, 3,4-dichloro-acetophenone-O-1′-(1′,3′,4′-triazolyl)-methaneoxime (4-DTM) and 2,5-dichloro-acetophenone-O-1′-(1′,3′,4′-triazolyl)-methaneoxime (5-DTM) were synthesized, and the inhibition effects for mild steel in 1 M HCl solutions were investigated by weight loss measurements, electrochemical tests and scanning electronic microscopy (SEM). The weight loss measurements showed that these compounds have excellent inhibiting effect at a concentration of 1.0 × 10⁻³ M. The potentiodynamic polarization experiment revealed that the triazole derivatives are inhibitors of mixed-type and electrochemical impedance spectroscopy (EIS) confirmed that changes in the impedance parameters (R _ct and C _dl) are due to surface adsorption. The inhibition efficiencies obtained from weight loss measurements and electrochemical tests were in good agreement. Adsorption followed the Langmuir isotherm with negative values of the free energy of adsorption . The thermodynamic parameters of adsorption were determined and are discussed. Results show that both 4-DTM and 5-DTM are good inhibitors for mild steel in acid media.     

Characterization of the Stereochemical Structures of 2H‐Thiazolo[3,2‐a]pyrimidine Compounds and Their Binding Affinities for Anti‐apoptotic Bcl‐2 Family Proteins

In a previous study we reported a class of compounds with a 2H‐thiazolo[3,2‐a]pyrimidine core structure as general inhibitors of anti‐apoptotic Bcl‐2 family proteins. However, the absolute stereochemical configuration of one carbon atom on the core structure remained unsolved, and its potential impact on the binding affinities of compounds in this class was unknown. In this study, we obtained pure R and S enantiomers of four selected compounds by HPLC separation and chiral synthesis. The absolute configurations of these enantiomers were determined by comparing their circular dichroism spectra to that of an appropriate reference compound. In addition, a crystal structure of one selected compound revealed the exocyclic double bond in these compounds to be in the Z configuration. The binding affinities of all four pairs of enantiomers to Bcl‐x_L, Bcl‐2, and Mcl‐1 proteins were measured in a fluorescence‐polarization‐based binding assay, yielding inhibition constants (K_i values) ranging from 0.24 to 2.20 μM . Interestingly, our results indicate that most R and S enantiomers exhibit similar binding affinities for the three tested proteins. A binding mode for this compound class was derived by molecular docking and molecular dynamics simulations to provide a reasonable interpretation of this observation.     

Aldimines — Effective Corrosion Inhibitors for Mild Steel in Hydrochloric Acid Solution

New and effective aldimine types of corrosion inhibitors namely, N-methylidene octylamine (MOA), N-ethylidene octylamine (EOA) and N-propylidene octylamine (POA) have been synthesized. Their inhibition efficiency was investigated for the corrosion of mild steel in 1 M HCl solution by various corrosion monitoring techniques. A preliminary screening of the inhibition efficiency of the inhibitors was carried out by weight loss and gasometric studies. They were found to behave as good inhibitors in 1 M HCl solution. Potentiodynamic polarization measurements show that aldimines are mixed type inhibitors. The extent of the decrease in the hydrogen permeation current through the mild steel surface was studied by the hydrogen permeation technique and it was found that the decrease was in the order POA > EOA > MOA. Double layer capacitance and charge transfer resistance values were derived from Nyquist plots obtained from AC impedance studies. The adsorption of these compounds on mild steel from 1 M HCl solution obeys the Temkin adsorption isotherm.     

Discovery of Novel Autophagy Inhibitors and Their Sensitization Abilities for Vincristine-Resistant Esophageal Cancer Cell Line Eca109/VCR

Resistance phenomena, especially acquired drug resistance, have been severely hampering the application of chemotherapeutics during cancer chemotherapy. Autophagy plays a role in maintaining the survival of cancer cells and might mediate resistance to chemotherapy drugs. Herein, a new series of 5-amino-2-ether-benzamide derivatives were synthesized and evaluated as autophagy inhibitors. Selected from 14 synthesized compounds as lead autophagy inhibitor, N-(cyclohexylmethyl)-5-(((cyclohexylmethyl)amino)methyl)-2-((4-(trifluoromethyl)benzyl)oxy)benzamide ( 4 d ) showed the most obvious effect of LC3B protein conversion. Further, its autophagy inhibition, evaluated by using transmission electron microscopy and confocal microscopy, showed that the fusion of autophagosomes and lysosomes in the final stage of autophagic flux was suppressed. We also found that 4 d could enhance the chemosensitivity of vincristine in vincristine-resistant esophageal cancer cell line Eca109/VCR in a synergistic, associative manner. Moreover, a computational study showed that 4 d might bind with p62-zz to inhibit autophagy. We also found 4 d to be relatively less cytotoxic to normal cells versus cancer cells than the reported p62-zz inhibitor.