Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase‐B (MAO‐B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO‐B (hMAO‐B) inhibitors, two series of twenty chalcones containing electron‐donating and electron‐withdrawing substituents were synthesized. All compounds were found to be competitive, selective, and reversible inhibitors of hMAO‐B except (2E)‐1‐(4‐methylphenyl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( P7 ) and (2E)‐1‐(4‐chlorophenyl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( P17 ), which were found to be selective inhibitors of hMAO‐A. The most potent hMAO‐B inhibitor, (2E)‐1‐(4‐chlorophenyl)‐3‐(4‐ethylphenyl)prop‐2‐en‐1‐one ( P16 ), showed a K_i value of 0.11±0.01 μm . Molecular docking simulations were carried out to identify the hypothetical binding mode for the most potent compounds in the active sites of hMAO‐A and B. The ability of the compounds to cross the blood–brain barrier was assessed by parallel artificial membrane permeability assay (PAMPA). Additionally, the most potent hMAO‐B inhibitor P16 showed no toxicity in cultured hepatic cells at concentrations of 5 and 25 μm .     

Benzofuran–Chalcone Hybrids as Potential Multifunctional Agents against Alzheimer’s Disease: Synthesis and in vivo Studies with Transgenic Caenorhabditis elegans

In the search for effective multifunctional agents for the treatment of Alzheimer’s disease (AD), a series of novel hybrids incorporating benzofuran and chalcone fragments were designed and synthesized. These hybrids were screened by using a transgenic Caenorhabditis elegans model that expresses the human β‐amyloid (Aβ) peptide. Among the hybrids investigated, (E)‐3‐(7‐methyl‐2‐(4‐methylbenzoyl)benzofuran‐5‐yl)‐1‐phenylprop‐2‐en‐1‐one ( 4 f ), (E)‐3‐(2‐benzoyl‐7‐methylbenzofuran‐5‐yl)‐1‐phenylprop‐2‐en‐1‐one ( 4 i ), and (E)‐3‐(2‐benzoyl‐7‐methylbenzofuran‐5‐yl)‐1‐(thiophen‐2‐yl)prop‐2‐en‐1‐one ( 4 m ) significantly decreased Aβ aggregation and increased acetylcholine (ACh) levels along with the overall availability of ACh at the synaptic junction. These compounds were also found to decrease acetylcholinesterase (AChE) levels, reduce oxidative stress in the worms, lower lipid content, and to provide protection against chemically induced cholinergic neurodegeneration. Overall, the multifunctional effects of these hybrids qualify them as potential drug leads for further development in AD therapy.     

Semi‐synthesis and Structure–Activity Relationship of Neuritogenic Oleanene Derivatives

(3S,4R)‐23,28‐Dihydroxyolean‐12‐en‐3‐yl (2E)‐3‐(3,4‐dihydroxyphenyl)acrylate ( 1 a ), which possesses significant neuritogenic activity, was isolated from the traditional Chinese medicine (TCM) plant, Desmodium sambuense. To confirm the structure and to assess biological activity, we semi‐synthesized 1 a from commercially available oleanolic acid. A series of novel 1 a derivatives was then designed and synthesized for a structure–activity relationship (SAR) study. All synthetic derivatives were characterized by analysis of spectral data, and their neuritogenic activities were evaluated in assays with PC12 cells. The SAR results indicate that the number and position of the hydroxy groups on the phenyl ring and the triterpene moiety, as well as the length of the (saturated or unsaturated) alkyl chain that links the phenyl ring with the triterpene critically influence neuritogenic activity. Among all the tested compounds, 1 e [(3S,4R)‐23,28‐dihydroxyolean‐12‐en‐3‐yl (2E)‐3‐(3,4,5‐trihydroxyphenyl)acrylate] was found to be the most potent, inducing significant neurite outgrowth at 1 μm .     

Synthesis and Biological Evaluation of Imidazo[2,1‐b][1,3,4]thiadiazole‐Linked Oxindoles as Potent Tubulin Polymerization Inhibitors

A series of imidazo[2,1‐b][1,3,4]thiadiazole‐linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti‐proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)‐5‐fluoro‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)‐imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), 11 ((E)‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), and 15 ((E)‐6‐chloro‐3‐((6‐phenyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one) exhibited potent anti‐proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G₂/M phase, inhibition of tubulin assembly, and increased cyclin‐B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC₅₀ range of 1.1–1.6 μM , and inhibited tubulin polymerization with an IC₅₀ value (0.15 μM ) lower than that of combretastatin A‐4 (1.16 μM ). Docking studies reveal that compounds 7 and 11 bind with αAsn101, βThr179, and βCys241 in the colchicine binding site of tubulin.     

Development of Second‐Generation Small‐Molecule RhoA Inhibitors with Enhanced Water Solubility,Tissue Potency,and Significant in vivo Efficacy

RhoA, a member of the Rho GTPases, is involved in a variety of cellular functions and could be a suitable therapeutic target for the treatment of cardiovascular diseases. However, few small‐molecule RhoA inhibitors have been reported. Based on our previously reported lead compounds, 32 new 2‐substituted quinoline (or quinoxaline) derivatives were synthesized and tested in biological assays. Six compounds showed high RhoA inhibitory activities, with IC₅₀ values of 1.17–1.84 μM . Among these, (E)‐3‐(3‐(ethyl(quinolin‐2‐yl)amino)phenyl)acrylic acid ( 26 b ) and (E)‐3‐(3‐(butyl(quinolin‐2‐yl)amino)phenyl)acrylic acid ( 26 d ) demonstrated noticeable vasorelaxation effects against phenylephrine‐induced contraction in thoracic aorta artery rings, and compound 26 b had good water solubility and showed significant in vivo efficacy, which was similar to that of 5‐(1,4‐diazepane‐1‐sulfonyl)isoquinoline (fasudil) in a subarachnoid hemorrhage–cardiovascular model. To the best of our knowledge, compound 26 b is the first example of a small‐ molecule RhoA inhibitor with potent in vivo efficacy, which could serve as a good lead for designing cardiovascular agents.     

Synthesis,Biological Activity,and Mechanism of Action of 2‐Pyrazyl and Pyridylhydrazone Derivatives,New Classes of Antileishmanial Agents

In this work, we report the antileishmanial activity of 23 compounds based on 2‐pyrazyl and 2‐pyridylhydrazone derivatives. The compounds were tested against the promastigotes of Leishmania amazonensis and L. braziliensis, murine macrophages, and intracellular L. amazonensis amastigotes. The most potent antileishmanial compound was selected for investigation into its mechanism of action. Among the evaluated compounds, five derivatives [(E)‐3‐((2‐(pyridin‐2‐yl)hydrazono)methyl)benzene‐1,2‐diol ( 2 b ), (E)‐4‐((2‐(pyridin‐2‐yl)hydrazono)methyl)benzene‐1,3‐diol ( 2 c ), (E)‐4‐nitro‐2‐((2‐(pyrazin‐2‐yl)hydrazono)methyl)phenol ( 2 s ), (E)‐2‐(2‐(pyridin‐2‐ylmethylene)hydrazinyl)pyrazine ( 2 u ), and (E)‐2‐(2‐((5‐nitrofuran‐2‐yl)methylene)hydrazinyl)pyrazine ( 2 v )] exhibited significant activity against L. amazonensis amastigote forms, with IC₅₀ values below 20 μm . The majority of the compounds did not show any toxic effect on murine macrophages. Preliminary studies on the mode of action of members of this hydrazine‐derived series indicate that the accumulation of reactive oxygen species (ROS) and disruption of parasite mitochondrial function are important for the pharmacological effect on L. amazonensis promastigotes.     

Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death

In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2–HDAC binding agents. Compound 3 [(E)‐N‐hydroxy‐5‐(3‐(4‐(3‐oxo‐3‐(pyridin‐3‐yl)prop‐1‐en‐1‐yl)phenyl)thioureido)pentanamide] emerged as the most interesting of the series, being able to inhibit TG2 and HDACs both in vitro (TG2 IC₅₀=13.3±1.5 μm , HDAC1 IC₅₀=3.38±0.14 μm , HDAC6 IC₅₀=4.10±0.13 μm ) and in cell‐based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μm and protects neurons against toxic insults induced by glutamate (5 mm ) with an EC₅₀ value of 3.7±0.5 μm .     

Synthesis and Biological Evaluation of Benzo[b]furans as Inhibitors of Tubulin Polymerization and Inducers of Apoptosis

A series of benzo[b]furans was synthesized with modification at the 5‐position of the benzene ring by introducing C‐linked substituents (aryl, alkenyl, alkynyl, etc.). These compounds were evaluated for their antiproliferative activities, inhibition of tubulin polymerization, and cell‐cycle effects. Some compounds in this series displayed excellent activity in the nanomolar range against lung cancer (A549) and renal cell carcinoma (ACHN) cancer cell lines. (6‐Methoxy‐5‐((4‐methoxyphenyl)ethynyl)‐3‐methylbenzofuran‐2‐yl)(3,4,5‐trimethoxyphenyl)methanone ( 26 ) and (E)‐3‐(6‐methoxy‐3‐methyl‐2‐(1‐(3,4,5‐trimethoxyphenyl)vinyl)benzofuran‐5‐yl)prop‐2‐en‐1‐ol ( 36 ) showed significant activity in the A549 cell line, with IC₅₀ values of 0.08 and 0.06 μM , respectively. G₂/M cell‐cycle arrest and subsequent apoptosis was observed in the A549 cell line after treatment with these compounds. The most active compound in this series, 36 , also inhibited tubulin polymerization with a value similar to that of combretastatin A‐4 (1.95 and 1.86 μM , respectively). Furthermore, detailed biological studies such as Hoechst 33258 staining, DNA fragmentation and caspase‐3 assays, and western blot analyses with the pro‐apoptotic protein Bax and the anti‐apoptotic protein Bcl‐2 also suggested that these compounds induce cell death by apoptosis. Molecular docking studies indicated that compound 36 interacts and binds efficiently with the tubulin protein.     

Mono‐, Di‐ and Tetra‐Cationic Surfactants as Carbon Steel Corrosion Inhibitors

Corrosion inhibition of three new synthesized cationic surfactants, N‐(2‐(((Z)‐4‐(pyridin‐4‐yl)but‐3‐en‐1‐yl)amino)ethyl)‐N‐(2‐((E)‐(pyridin‐4‐ylmethylene)amino)ethyl)dodecan‐1‐aminium bromide I(4N), N¹,N²‐didodecyl‐N¹‐((Z)‐4‐(pyridin‐4‐yl)but‐3‐en‐1‐yl)‐N²‐(2‐((E)‐(pyridin‐4‐ylmethylene)amino)ethyl)ethane‐1,2‐diaminium bromide II(4N) and 1‐dodecyl‐4‐((E)‐((2‐(dodecyl(2‐(dodecyl((Z)‐4‐(1‐dodecylpyridin‐1‐ium‐4‐yl)but‐3‐en‐1‐yl)ammonio)ethyl)ammonio)ethyl)imino)methyl)pyridin‐1‐ium bromide IV(4N) on carbon steel was investigated by weight loss, electrochemical impedance spectroscopy and polarization measurements. Results show that the synthesized cationic surfactants inhibit corrosion of carbon steel in 1 M HCl. The inhibitive action occurs by virtue of adsorption on the metal surface following a Langmuir adsorption isotherm model. Polarization curves reveal that the investigated cationic surfactants can be classified as mixed inhibitor types. The variations in the corrosion inhibition efficiency between three cationic surfactants are correlated with their chemical structures, with more hydrophobic surfactants yielding higher inhibition efficiency.     

Isoxazole‐Based‐Scaffold Inhibitors Targeting Cyclooxygenases (COXs)

A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline, two moieties typical of efflux pump substrates and inhibitors, respectively. Among all the synthesized compounds, two new COX inhibitors with opposite selectivity were discovered: compound 8 [N‐(9‐{2‐[(4‐{2‐[3‐(5‐chlorofuran‐2‐yl)‐4‐phenylisoxazol‐5‐yl]acetamido}butyl)carbamoyl]phenyl‐6‐(ethylamino)‐2,7‐dimethyl‐3H‐xanthen‐3‐ylidene}ethanaminium chloride] was found to be a selective COX‐1 inhibitor, whereas 17 (2‐[3,4‐bis(4‐methoxyphenyl)isoxazol‐5‐yl]‐1‐[6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2‐(1H)‐yl]ethanone) was found to be a sub‐micromolar selective COX‐2 inhibitor. However, both were shown to interact with P‐glycoprotein. Docking experiments helped to clarify the molecular aspects of the observed COX selectivity.     

Synthesis and characterization of macroporous silica modified with optically active poly[N‐(oxazolinylphenyl)acrylamide] derivatives for potential application as chiral stationary phases

Enantiopure acrylamide derivatives, (S)‐N‐[o‐(4‐methyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl]acrylamide and (R)‐N‐[o‐(4‐phenyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl]acrylamide, were synthesized through the acylation of chiral 2‐oxazolinylanilines. The radical polymerization of the chiral monomers was carried out with (3‐mercaptopropyl)trimethoxysilane as a chain‐transfer agent to obtain the corresponding optically active prepolymers with a trimethoxysilyl group. By immobilizing the prepolymers on porous silica gel via the grafting‐to method, we prepared a new chiral stationary phase (CSP) and characterized it by elemental analysis, thermogravimetry, and Fourier transform infrared spectroscopy. The enantioseparation capacities of the CSPs were evaluated with high‐performance liquid chromatography toward several racemic compounds, including 1,1′‐bi‐2‐naphthol, benzoin, 2‐amino‐1‐butanol, and loxoprofen sodium under the normal‐phase mode. The results indicate that the CSPs exhibited improved chromatographic performances compared to their brush‐type analogs obtained by the alternative grafting‐from approach. Also, the column packed with poly{(R)‐N‐[o‐(4‐phenyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl]acrylamide}‐bonded silica was found to have an extent of enantioselectivity in the chiral resolution of some unmodified amino acids with reversed‐phase eluents. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

A series of chalcone conjugates featuring the imidazo[2,1‐b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF‐7, A549, HeLa, DU‐145 and HT‐29). These new hybrid molecules have shown promising cytotoxic activity with IC₅₀ values ranging from 0.64 to 30.9 μM . Among them, (E)‐3‐(6‐(4‐fluorophenyl)‐2,3‐bis(4‐methoxyphenyl)imidazo[2,1‐b]thiazol‐5‐yl)‐1‐(pyridin‐2‐yl)prop‐2‐en‐1‐one ( 11 x ) showed potent antiproliferative activity with IC₅₀ values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate ( 11 x ) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell‐cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase‐3, DNA fragmentation analysis, and Annexin V–FITC assay. Moreover, molecular docking studies indicated that this conjugate ( 11 x) interacts and binds efficiently with the tubulin protein.     

The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 1

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol–Myers–Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl‐imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)‐1‐((S)‐2‐(4‐(4‐(6‐(2‐((S)‐1‐((methoxycarbonyl)‐L ‐valyl)pyrrolidin‐2‐yl)‐1H‐imidazol‐5‐yl)quinoxalin‐2‐yl)phenyl)‐1H‐imidazol‐2‐yl)pyrrolidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)carbamate ( 17 ), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half‐life. This compound represents a promising lead that warrants further evaluation.     

From Type I to Type II: Design,Synthesis, and Characterization of Potent Pyrazin‐2‐ones as DFG‐Out Inhibitors of PDGFRβ

Reversible protein kinase inhibitors that bind in the ATP cleft can be classified as type I or type II binders. Of these, type I inhibitors address the active form, whereas type II inhibitors typically lock the kinase in an inactive form. At the molecular level, the conformation of the flexible activation loop holding the key DFG motif controls access to the ATP site, thereby determining an active or inactive kinase state. Accordingly, type I and type II kinase inhibitors bind to so‐called DFG‐in or DFG‐out conformations, respectively. Based on our former study on highly selective platelet‐derived growth factor receptor β (PDGFRβ) pyrazin‐2‐one type I inhibitors, we expanded this scaffold toward the deep pocket, yielding the highly potent and effective type II inhibitor 5 (4‐[(4‐methylpiperazin‐1‐yl)methyl]‐N‐[3‐[[6‐oxo‐5‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrazin‐3‐yl]methyl]phenyl]benzamide). In vitro characterization, including selectivity panel data from activity‐based assays (300 kinases) and affinity‐based assays (97 kinases) of these PDGFRβ type I ( 1 ; 5‐(4‐hydroxy‐3‐methoxy‐phenyl)‐3‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrazin‐2‐one) and II ( 5 ) inhibitors showing the same pyrazin‐2‐one chemotype are compared. Implications are discussed regarding the data for selectivity and efficacy of type I and type II ligands.     

Coupled Biosynthesis of Volatiles and Salinosporamide A in Salinispora tropica

Terrestrial bacteria, especially actinomycetes, are known to be prolific producers of volatile compounds. We show here that bacteria from ocean sediments can also release complex bouquets of volatiles. The actinomycete Salinispora tropica produces cyclohexenyl compounds not previously known in nature, such as methyl cyclohex‐2‐ene‐1‐carboxylate ( 9 ), methyl 2‐(cyclohex‐2‐en‐1‐yl)acetate ( 10 ), methyl (E/Z)‐2‐(cyclohex‐2‐en‐1‐ylidene)acetate ( 11 / 12 ), and related alcohols 8 and 13 . These compounds were identified by GC/MS and confirmed by synthesis. In addition, rare spiroacetals, aromatic compounds, short‐chain acids and esters, alcohols, and various cyclic compounds were produced by the bacteria. The biosynthesis of the cyclohexenyl compounds is closely coupled to that of cyclohexenylalanine ( 4 ), a building block of salinosporamide A, a proteasome inhibitor produced by S. tropica. Analysis of S. tropica strains that harbor knockouts of the salinosporamide biosynthetic genes salX and salD, coupled with feeding experiments, revealed that 3‐(cyclohex‐2‐en‐1‐yl)‐2‐oxopropanoic acid ( 60 ) and 3‐(cyclohex‐2‐en‐1‐ylidene)‐2‐oxopropanoic acid (isomers 61 and 62 ) are important intermediates in the biosynthesis of salinosporamide A, 4 , and 8 – 13 .     

Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action

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.     

Discovery of MK‐8742: An HCV NS5A Inhibitor with Broad Genotype Activity

The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK‐4882 [2‐((S)‐pyrrolidin‐2‐yl)‐5‐(2‐(4‐(5‐((S)‐pyrrolidin‐2‐yl)‐1H‐imidazol‐2‐yl)phenyl)benzofuran‐5‐yl)‐1H‐imidazole]. While preclinical proof‐of‐concept studies in HCV‐infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single‐ and multiple‐dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK‐4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK‐8742, a tetracyclic indole‐based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all‐oral, interferon‐free regimen for the treatment of HCV infection.     

Synthese des 5‐[(Acetylhydrazono)‐(4‐chlorphenyl)‐methyl]thiophen‐2‐yl‐esters der Trifluormethansulfonsäure

The synthesis of 5‐[(acetylhydrazono)‐(4‐chlorophenyl)‐methyl]thiophen‐2‐yl ester of the trifluoromethanesulfonic acid ( 2a ) and its N‐methyl derivative 2b was attempted. Oxidation of 2‐thiophene boronic acid to 2‐hydroxythiophene and in situ reaction there of with triflic anhydride yielded the hitherto unknown thiophene‐2‐yl ester of the trifluormethanesulfonic acid ( 6 ) which was transformed under Friedel‐Crafts conditions into 5‐(4‐chlorobenzoyl)‐thiophene‐2‐yl ester of the trifluoromethanesulfonic acid ( 3 ). Reaction of 3 with acetyl hydrazine resulted in the formation of the title compound 2a , albeit in low yield. The conversion of N′‐[(5‐bromothiophen‐2‐yl)‐(4‐chlorophenyl)‐methylen]‐N‐methylhydrazide ( 4b ) via boronic acid into 5‐[(acetylmethylhydrazono)‐(4‐chlorophenyl)‐methyl]thiophen‐2‐yl ester of the trifluoromethanesulfonic acid ( 2b ) was not successful.     

Structure‐Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain

In this study we explored the pharmaceutically underexploited ATPase domain of DNA gyrase (GyrB) as a potential platform for developing novel agents that target Mycobacterium tuberculosis. In this effort a combination of ligand‐ and structure‐based pharmacophore modeling was used to identify structurally diverse small‐molecule inhibitors of the mycobacterial GyrB domain based on the crystal structure of the enzyme with a pyrrolamide inhibitor (PDB ID: 4BAE ). Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound 5 [(E)‐5‐(5‐(2‐(1H‐benzo[d]imidazol‐2‐yl)‐2‐cyanovinyl)furan‐2‐yl)isophthalic acid; IC₅₀=4.6±0.1 μm ], which was subsequently tailored through a combination of molecular modeling and synthetic chemistry to yield the optimized lead compound 24 [(E)‐3‐(5‐(2‐cyano‐2‐(5‐methyl‐1H‐benzo[d]imidazol‐2‐yl)vinyl)thiophen‐2‐yl)benzoic acid; IC₅₀=0.3±0.2 μm ], which was found to display considerable in vitro efficacy against the purified GyrB enzyme and potency against the H₃₇Rv strain of M. tuberculosis. Structural handles were also identified that will provide a suitable foundation for further optimization of these potent analogues.