Inhibitors of HCV NS5B polymerase: synthesis and structure-activity relationships of N-1-heteroalkyl-4-hydroxyquinolon-3-yl-benzothiadiazines

N-1-Alkylamino and N-1-alkyloxy-4-hydroxyquinolon-3-yl benzothiadiazines were synthesized and evaluated as inhibitors of genotype 1 HCV polymerase. The N-1-alkyloxy derivatives were not potent inhibitors, however N-1-alkylamino derivatives displayed comparable potency to carbon analogs. Analogs with aliphatic substituents were significantly more potent than those with benzylic substituents against genotype 1a polymerase. The most potent inhibitors contained small alkyl or carbocyclic substituents and exhibited IC50's of 50-100 and 200-400 nM against genotype 1b and 1a HCV polymerase, respectively.     

Cysteine based novel noncompetitive inhibitors of urease(s)--distinctive inhibition susceptibility of microbial and plant ureases

Based on the catalysis mechanism of urease, a homologous series of 10 cysteine derivatives (CysDs) was designed and synthesized, and their inhibitory activities were evaluated for microbial ureases (Bacillus pasteurii, BPU, and Proteus mirabilis, PMU) and for a plant urease [jack bean (Cavavalia ensiformis), JBU]. As already described, thiol-compounds might inhibit urease activity by chelating the nickel atoms involved in the catalysis process. In contrast to cysteine, which has been reported to be a very weak urease inhibitor, we verified a potential inhibitory activity of these CysDs. The kinetic data demonstrate that thiol derivatives are more effective than the respective thioether derivatives. Besides, thiol-CysDs had a reduced activity in acidic pH (5.0). Lineweaver-Burk plots indicated that the nature of inhibition was of noncompetitive type for all 10 compounds, with the minimum Ki value of 2 microM for N,N-dimethyl L-cysteine. It is proposed that these classes of compounds are more potent inhibitors of the bacterial ureases, compared with the plant-originated urease. Since microbial urease is directly involved in the infection process of many pathological organisms, this work demonstrates that thiol-CysDs represent a class of new potential urease inhibitors.     

Synthesis of hydroxypyrone- and hydroxythiopyrone-based matrix metalloproteinase inhibitors: Developing a structure–activity relationship

The zinc(II)-dependent matrix metalloproteinases (MMPs) are associated with a variety of diseases. Development of inhibitors to modulate MMP activity has been an active area of investigation for therapeutic development. Hydroxypyrones and hydroxythiopyrones are alternative zinc-binding groups (ZBGs) that, when combined with peptidomimetic backbones, comprise a novel class of MMP inhibitors (MMPi). In this report, a series of hydroxypyrone- and hydroxythiopyrone-based MMPi with aryl backbones at the 2-, 5-, and 6-positions of the hydroxypyrone ring have been synthesized. Synthetic routes for developing inhibitors with substituents at two of these positions (so-called double-handed inhibitors) are also explored. The MMP inhibition profiles and structure–activity relationship of synthesized hydroxypyrones and hydroxythiopyrones have been analyzed. The results here show that the ZBG, the position of the backbone on the ZBG, and the nature of the linker between the ZBG and backbone are critical for MMPi activities.     

Pyridazine based inhibitors of p38 MAPK

Trisubstituted pyridazines were synthesized and evaluated as in vitro inhibitors of p38MAPK. The most active isomers were those possessing an aryl group alpha and a heteroaryl group beta relative to the nitrogen atom in the 2-position of the central pyridazine. Additionally, substitution in the 6-position of the central pyridazine with a variety of dialkylamino substituents afforded a set of inhibitors having good (p38 IC50 1-20 nM) in vitro activity.     

Synthesis and urease enzyme inhibitory effects of some dicoumarols

Dicoumarols 1-10 with substituted phenyl residues at C-11 were synthesized and screened for their urease inhibition effects. All synthesized compounds showed varying degree of urease inhibitory activity ranging from IC50 = 74.30-91.35 microM.     

A new series of N2-substituted-5-(p-toluenesulfonylamino)phthalimide analogues as α-glucosidase inhibitors

Several members of a new family of non-sugar-type α-glycosidase inhibitors, bearing a 5-(p-toluenesulfonylamino)phthalimide moiety and various substituent at the N2 position, were synthesized and their activities were investigated. The newly synthesized compounds displayed different inhibition profile towards yeast α-glycosidase and rat intestinal α-glycosidase. Almost all the compounds had strong inhibitory activities against yeast α-glycosidase. Regarding rat intestinal α-glycosidase, only analogs with N2-aromatic substituents displayed varying degrees of inhibitory activities on rat intestinal maltase and lactase and nearly all compounds showed no inhibition against rat intestinal α-amylase. Structure–activity relationship studies indicated that 5-(p-toluenesulfonylamino)phthalimide moiety is a favorable scaffold to exert the α-glucosidase inhibitory activity and substituents at the N2 position have considerable influence on the efficacy of the inhibition activities.     

The physiological implications of urease inhibitors on N metabolism during germination of Pisum sativum and Spinacea oleracea seeds

The development of new nitrogen fertilizers is necessary to optimize crop production whilst improving the environmental aspects arising from the use of nitrogenous fertilization as a cultural practice. The use of urease inhibitors aims to improve the efficiency of urea as a nitrogen fertilizer by preventing its loss from the soil as ammonia. However, although the action of urease inhibitors is aimed at the urease activity in soil, their availability for the plant may affect its urease activity. The aim of this work was therefore to evaluate the effect of two urease inhibitors, namely acetohydroxamic acid (AHA) and N-(n-butyl) thiophosphoric triamide (NBPT), on the germination of pea and spinach seeds. The results obtained show that urease inhibitors do not affect the germination process to any significant degree, with the only process affected being imbibition in spinach, thus also suggesting different urease activities for both plants. Our findings therefore suggest an activity other than the previously reported urolytic activity for urease in spinach. Furthermore, of the two inhibitors tested, NBPT was found to be the most effective at inhibiting urease activity, especially in pea seedlings.     

Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors

We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC(50)=19 nM), respectively. The synthesis and SAR of these compounds are described.     

Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists

Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition.     

Syntheses,in vitro urease inhibitory activities of urea and thiourea derivatives of tryptamine,their molecular docking and cytotoxic studies

Urease is an enzyme of amidohydrolase family and is responsible for the different pathological conditions in the human body including peptic ulcers, catheter encrustation, kidney stone formation, hepatic coma, encephalopathy, and many others. Therefore, the search for potent urease inhibitors has attracted major scientific attention in recent years. Urea and thiourea derivatives of tryptamine (1–25) were synthesized via reaction of tryptamine with different substituted phenyl isocyanates/isothiocyanates. The synthetic compounds were evaluated for their urease enzyme inhibitory activity and they exhibited good inhibitory potential against urease enzyme in the range of (IC₅₀ = 11.4 ± 0.4–24.2 ± 1.5 μM) as compared to the standard thiourea (IC₅₀ = 21.2 ± 1.3 μM). Out of twenty-five compounds, fourteen were found to be more active than the standard. Limited structure-activity relationship suggested that the compounds with CH₃, and OCH₃ substituents at aryl part were the most potent derivatives. Compound 14 (IC₅₀ = 11.4 ± 0.4 μM) with a methyl substituent at ortho position was found to be the most active member of the series. Whereas, among halogen substituted derivatives, para substituted chloro compound 16 (IC₅₀ = 13.7 ± 0.9 μM) showed good urease inhibitory activity. These synthetic derivatives were found to be non-cytotoxic in cellular assay. Kinetic studies revealed that the compounds 11, 12, 14, 17, 21, 22, and 24 showed a non-competitive type of inhibition. In silico study identified the possible bindings interactions of potential inhibitors with the active site of enzyme. These newly identified inhibitors of urease enzyme can serve as leads for further research and development.     

Synthesis and SAR of hydroxyethylamine based phenylcarboxyamides as inhibitors of BACE

A series of N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(3-methoxybenzylamino)-butan-2-yl)benzamides has been synthesized as BACE inhibitors. A variety of P2 and P3 substituents has been explored, and these efforts have culminated in the identification of several 1,3,5-trisubstituted phenylcarboxyamides with potent BACE inhibitory activity.     

Synthesis,Biological Activity Evaluation,Docking and Molecular Dynamics Studies of New Triazole-Tetrahydropyrimidinone(thione) Hybrid Scaffolds as Urease Inhibitors

New series of triazole-tetrahydropyrimidinone(thione) hybrids ( 9a – g ) were synthesized. FT-IR, ¹H-NMR, ¹³C-NMR, elemental analysis and mass spectroscopic studies characterized the structures of the synthesized compounds. Then, the synthesized compounds were screened to determine the urease inhibitory activity. Methyl 4-(4-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ( 9c ) exhibited the highest urease inhibitory activity (IC₅₀=25.02 μM) among the compounds which was almost similar to thiourea as standard (IC₅₀=22.32 μM). The docking study of the screened compounds demonstrated that these compounds fit well in the urease active site. Based on the docking study, compound 9c with the highest urease inhibitory activity showed chelates with both Ni²⁺ ions of the urease active site. Moreover, the molecular dynamic study of the most potent compounds showed that they created important interactions with the active site flap residues, His322, Cys321, and Met317.     

Monoamine oxidase inhibition by N-alkyloxycarbonyl derivatives of ethylene diamine

Urethane type derivatives of ethylene diamine (EDA) were synthesized and tested as inhibitors of rat liver mitochondrial monoamine oxidase (MAO) A and B. The nature of the aromatic ring and the position of substituents in it were crucial for manifestation of the inhibitory activity. 3,4- and 2,4-Chlorobenzyloxycarbonyl-EDA derivatives were the most potent MAO A inhibitors. The inhibition of both MAO A and to a lesser extent MAO B depended on preincubation time with these inhibitors. The activity of both enzymes did not recover completely after repeated sedimentation and resuspension of inhibitor-treated mitochondria. The data suggest that these compounds exhibit properties of tight-binding reversible inhibitors of MAO A and B. The development of a new generation of MAO inhibitors causing simultaneous reversible nonselective inhibition of MAO A and B must meet one important criterion, the same type of inhibition of both the enzymes.     

Synthesis,Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4‐Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate

A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2‐(2‐hydroxyphenyl)‐4H‐benzo[e][1,3]oxazin‐4‐one. For the first time, deferasirox and some of its derivatives were evaluated for their in vitro inhibitory activity against Jack bean urease. The potencies of the members of this class of compounds are higher than that of acetohydroxamic acid. Two compounds, bearing tetrazole and hydrazine derivatives (bioisoester of carboxylate group), represented the most potent urease inhibitory activity with IC₅₀ values of 1.268 and 3.254 μm , respectively. In silico docking studies were performed to delineate possible binding modes of the compounds with the enzyme, urease. Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its crucial amino acid residues, CME592 and His593. The overall results of urease inhibition have shown that these target compounds can be further optimized and developed as a lead skeleton for the discovery of novel urease inhibitors     

Kinetics of novel competitive inhibitors of urease enzymes by a focused library of oxadiazoles/thiadiazoles and triazoles

Based on structure of the substrate of urease and for the purpose of designing pharmacophore models for urease inhibitors, which could be effective in physiological and pharmacological studies, a series of twenty-five 1,3,4-diazole-2(3H)-thiones-2(3H)-thiones, 1,3,4-diazoles-2(3H)-thiones, and 1,2,4-tri-3-thiones (OSNs) were designed, synthesized, and evaluated for various kinetic parameters of urease inhibition. OSNs inhibited the activity of urease(s) in a concentration dependent fashion. Dixon as well as Lineweaver-Burk plots and their secondary replots indicated that the nature of inhibition was of pure competitive type for all the 25 compounds. 5-[4-(hydroxy)phenyl]-1,3,4-thiadiazole-2(3H)-thione was found to be the most active one with a Ki value of 2 microM. The Ki values were increased with an increase in substrate concentrations. Apparently, OSNs employ a homologous mechanism of action by exploiting a common transition catalysis state and acting as ligand chelators to form octahedral complexes with the urease enzymes in an orientation-specific mode. The inhibition was slightly potentiated by lower pH and not abolished in the presence of NH2OH (a scavenger of histidine residue). Because of their safe profile in the genotoxic assay, they may be pursued in the near future for human testing     

Synthesis and molecular docking study of some novel 2,3-disubstituted quinazolin-4(3H)-one derivatives as potent inhibitors of urease

A new series of 2,3-disubstituted quinazolin-4(3H)-one compounds including oxadiazole and furan rings was synthesized. Their inhibitory activities on urease were assessed in vitro. All newly synthesized compounds exhibited potent urease inhibitory activity in the range of IC₅₀ = 1.55 ± 0.07–2.65 ± 0.08 µg/mL, when compared with the standard urease inhibitors such as thiourea (IC₅₀ = 15.08 ± 0.71 µg/mL) and acetohydroxamic acid (IC₅₀ = 21.05 ± 0.96 µg/mL). 2,3-Disubstituted quinazolin-4(3H)-one derivatives containing furan ring (3a-e) were found to be the most active inhibitors when compared with the compounds 2a-e bearing oxadiazole ring. Compound 3a, bearing 4-chloro group on phenyl ring, was found as the most effective inhibitor of urease with the IC₅₀ value of 1.55 ± 0.11 µg/mL. The molecular docking studies of the newly synthesized compounds were performed to identify the probable binding modes in the active site of the Jack bean urease (JBU) enzymes.     

2-heterosubstituted-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl pyridines as selective and orally active cyclooxygenase-2 inhibitors.

A series of novel 2-alkoxy, 2-thioalkoxy and 2-amino-3-(4-methylsulfonyl)phenylpyridines has been synthesized and shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. Structure-activity relationship studies have demonstrated that central pyridine ring substituents play an important role in the COX-2 potency, selectivity vs the COX-1 enzyme, and oral activity.     

Polyamines and the NMDA receptor: modifying intrinsic activities with aromatic substituents

Thirty-four spermidine (SPD) and spermine (SPM) derivatives with aromatic substituents were synthesized and tested as inhibitors of specific binding of the NMDA channel blocker [3H]MK-801 to membranes prepared from rat hippocampus and cerebral cortex. SPD and SPM derivatives with aromatic substituents at the primary amino groups were the most potent inhibitors (IC50 3.9-4.7 microM). These compounds most likely act directly at the NMDA ion channel, since 30 microM SPM had no pronounced influence on their inhibiting activities. SPD derivatives with aromatic substituents at the secondary amino group were either inactive or highly SPM-sensitive inhibitors (IC50 10-82 microM), depending on the size of the substituent. Our results support the hypothesis that an aromatic interaction site near the center of polyamine derivatives contributes to polyamine inverse agonism.     

Highly potent inhibitors of the Grb2-SH2 domain

Highly potent inhibitors of the Grb2-SH2 domain have been synthesized. They share the common sequence: Ac-Pmp-Ac6c-Asn-NH-(3-indolyl-propyl). Different substituents at the 3-indolyl-propylamine C-terminal group were explored to further improve the activity. This is the first example of inhibitors of SH2 domains with sub-nanomolar affinity reported to date.     

The synthesis and evaluation of phenoxyacylhydroxamic acids as potential agents for Helicobacter pylori infections

Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC₅₀?=?0.061?±?0.003?μM) and intact cell (IC₅₀?=?0.89?±?0.05?μM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds.