Angiotensin-converting enzyme inhibitors: synthesis and structure-activity relationships of potent N-benzyloxycarbonyl tripeptide inhibitors

A new series of gamma-D-Glu-containing N-benzyloxycarbonyl (Z) tripeptide inhibitors of angiotensin-converting enzyme (ACE) was synthesized. The effect of varying the antepenultimate amino acid residue in this series on the biological activity was studied. Introduction of Lys and Orn residues at the P1 position provided the most potent inhibitors, 25a and 25b (IC50: 3.5 and 4.9 x 10(-9) M, respectively), which exhibited an oral antihypertensive activity. This result suggests that basic amino acid residues at the P1 position play an important role in binding with the S1 subsite of ACE in this series. Oral antihypertensive activity of selected compounds was evaluated.     

Studies on angiotensin converting enzyme inhibitors. VI. Synthesis and angiotensin converting enzyme inhibitory activities of the dicarboxylic acid derivative of imidapril and its diastereoisomers.

All possible diastereoisomers of the dicarboxylic acid (10a), the biologically active form of imidapril (1), were synthesized, and their inhibitory activity against angiotensin converting enzyme (ACE) was examined. The in vitro ACE inhibitory activity of these compounds greatly depended on the configurations of the three asymmetric carbons in each molecule. The (S,S,S) isomer (10a) showed much more potent activity than the others.     

Microwave-assisted synthesis and biological evaluation of new thiazolylhydrazone derivatives as tyrosinase inhibitors and antioxidants

In this work, we have synthesized a series of 2-thiazolylhydrazone derivatives ( 1–27 ) and investigated their biological activities as tyrosinase inhibitors and antioxidants. Some compounds showed potent tyrosinase inhibitory activities and 4-(2-(2-(1-(4-Aminophenyl)ethylidene)-hydrazinyl)thiazol-4-yl) phenol ( 26 ) showed more potent inhibitory effect than the standard tyrosinase inhibitor kojic acid (IC₅₀: 9.8 μM vs. 23.6 μM). Compounds 2 , 14 , and 26 exhibited high antioxidant activities in 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. The structure–activity relationship (SAR) indicated that the substitutions of bromine, hydroxyl group, and amino groups cause great effect to the inhibition effect against tyrosinase. The mechanism and kinetic studies demonstrated that the inhibitory effect of compound 26 on the tyrosinase by acting as the reversible and uncompetitive inhibitor. Docking studies suggests that compound 26 interacts strongly with mushroom tyrosinase via hydrogen bonding.     

Indoline derivatives I: synthesis and factor Xa (FXa) inhibitory activities

A series of bisamidine derivatives each having a ring structure in the center of the molecule was synthesized and their Factor Xa (FXa) inhibitory activities were evaluated. Among them, some indoline derivatives showed potent inhibitory activities in vitro. In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a. Furthermore, (R)-18a exhibited more potent anticoagulant activity than DX-9065a. We also succeeded in obtaining an X-ray crystal structure of FXa bound with (R)-18a.     

Cinnamylindoline derivatives: synthesis and factor Xa (FXa) inhibitory activities

A series of cinnamylindoline derivatives were synthesized, and their factor Xa (FXa) inhibitory activities and selectivity over trypsin were evaluated. Among them, some novel derivatives showed potent FXa inhibitory activities and good selectivity over trypsin. Especially, (E)-2-{5-[1-(acetimidoyl)piperidin-4-yloxy]-2-[2-(5-amidino-2-hydroxyphenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic acid (22f) having 2-hydroxycinnamyl moiety exhibited the most potent FXa inhibitory activity in vitro. Furthermore, 22f also exhibited potent anticoagulant activities in vitro.     

Synthesis and structure-activity relationships of substituted 2-[(2-imidazolylsulfinyl)methyl]anilines as a new class of gastric H+/K(+)-ATPase inhibitors. II.

A series of 2-[(2-imidazolylsulfinyl)methyl]anilines (2) having various substituents on their imidazole and aniline rings was synthesized and examined for their H+/K(+)-ATPase (adenosine triphosphatase) inhibitory effects and antisecretory activity against histamine-stimulated gastric acid secretions in Heidenhain pouch dogs. Although substitutions on the imidazole ring did not enhance biological activity, substitutions on the aniline ring by electron-donating substituents potently enhanced the enzyme inhibitory activity and also showed an inhibitory effect on histamine-stimulated gastric acid secretion after oral administration. In particular, the in vitro activity of the dimethyl (2u--w) and trimethyl (2ac) derivatives was about 10 times that of omeprazole. Also, 4-methyl (2k), 4-methoxy-5-methyl (2y) and 3,5-dimethyl-4-methoxy (2ab) derivatives showed a potent antisecretory effect of more than 80% after oral administration at 6 mg/kg. Although these aniline derivatives have relatively low stabilities in aqueous solution, replacement of the isobutyl group at the aniline nitrogen atom with N-(2-methoxyethyl) group enhanced the stability.     

Synthesis and antihypertensive activity of 1,4-dihydropyridine derivatives with a 4-(disubstituted phenyl) ring and an aminoalkyl ester group: highly potent and long-lasting calcium antagonists.

New 1,4-dihydropyridine derivatives bearing a 4-(disubstituted phenyl) ring and an aminoethyl ester or an amino-2,2-dimethyl-propyl ester were synthesized and their antihypertensive activities were examined in normotensive rats and spontaneously hypertensive rats. The effects of phenyl substituents and ester groups on the antihypertensive activity are discussed. Several compounds showed a more potent antihypertensive activity than nicardipine and most compounds had a longer duration of action. Among them, 7B.HCl (TC-81) showed highly potent and long-lasting activity and was selected as a candidate for further pharmacological investigations.     

Synthesis and calcium antagonistic activity of (+)-(R)- and (-)-(S)-3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5- trimethoxyphenethyl)amino]butoxy]phenyl]benzothiazoline hydrochloride

SA2572 ((+)-1), 3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5-trimethoxyphenethyl) amino] butoxy]phenyl]-benzothiazoline hydrochloride is a newly synthesized Ca2+ antagonist having a inhibitory effect on the fast Na+ inward channel. In order to clarify the absolute configurations and the pharmacological properties of both enantiomers, compounds ((+)-1 and (-)-1) were synthesized. The configurations of these compounds were assigned on the basis of an X-ray crystallographic analysis of synthetic precursor (5). The in vitro Ca2+ channel blocking activities of (+)-1 and (-)-1 were evaluated in terms of the inhibitory activities on depolarization-induced contraction of guinea pig taenia cecum and rabbit aorta. The in vivo efficacy of the enantiomers was evaluated with their hypotensive effects in spontaneously hypertensive rats. Compound (-)-1 showed more potent Ca2+ antagonistic activities on guinea pig taenia cecum and rabbit aorta and the hypotensive effect than those activities of (+)-1. In the electrophysiological study of Langendorff perfused rabbit hearts, compound (+)-1 showed more potent inhibitory effect on the fast Na+ inward channel than that of compound (-)-1, and an approximately equal potent inhibitory effect on the slow Ca2+ inward channel as compared with compound (-)-1. Stereoselectivity of the pharmacological activity was found.     

Synthesis of eosinophil infiltration inhibitors with antihistaminic activity

A series of [1, 2, 4]triazolo[1, 5-b]pyridazines (5) and imidazo[1, 2-b]pyridazines (6) having cyclic amines was synthesized and evaluated for antihistaminic activity and inhibitory effect on eosinophil infiltration. When a piperidine or a piperazine containing a benzhydryl group and a suitable spacer was incorporated at the 6-position, the fused pyridazines were found to exhibit both antihistaminic activity and an inhibitory effect on eosinophil chemotaxis. Above all, 6a showed potent antihistaminic activity, but little blockade of central H(1) receptors in contrast with its complete blockade of peripheral H(1) receptors as determined by an ex vivo binding assay. Furthermore, 6a inhibited eosinophil infiltration of the skin caused by a topical antigen challenge in sensitized guinea pigs, while an antihistamine terfenadine was not effective. After the pharmacokinetic study, 6a was found to be rapidly hydrolyzed to 6o, which was also orally active. Compound 6o, 2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1, 2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate (TAK-427), having both antihistaminic and antiinflammatory activity, is currently undergoing clinical trials as a therapeutic agent for atopic dermatitis and allergic rhinitis.     

Synthesis and biological activity of N-(aminoiminomethyl)-1H-indole carboxamide derivatives as Na+/H+ exchanger inhibitors

A series of N-(aminoiminomethyl)-1H-indole carboxamide derivatives were synthesized and their inhibitory potencies against the Na+/H+ exchanger were measured. Variation of the carbonylguanidine group at the 2- to 7-position of the indole ring system showed that a substitution at the 2-position improved the Na+/H+ exchanger inhibitory activity the most in vitro. This led to the synthesis and evaluation of an extensive series of N-(aminoiminomethyl)-1H-indole-2-carboxamide derivatives. Derivatives having an alkyl or substituted alkyl group at the 1-position of the indole ring system showed higher levels of in vitro activities. N-(aminoiminomethyl)- 1-(2-phenylethyl)-1H-indole-2-carboxamide (49) had the strongest activity.     

Synthesis and biological evaluation of substituted indazolyl amide derivatives as S-adenosyl-L-homocysteine hydrolase inhibitors

A series of novel amide derivatives bearing an indazole moiety were synthesized and evaluated for their in vitro S-adenosyl-L-homocysteine hydrolase (SAHase) inhibitory activity. Among these compounds, 8b, 8m, 8r and 8w showed better or similar inhibitory effects compared to the positive control aristeromycin. These results provide a novel lead for the discovery of more potent non-adenosine analogs as SAHase inhibitors.     

N-substituted hydroxyureas as urease inhibitors

In order to seek a urease inhibitor more potent than hydroxyurea (1), its alkyl- or phenyl-substituted derivatives were synthesized and evaluated for their effect on the jack bean urease. Of 16 compounds tested, m-methyl- (10) and m-methoxy-phenyl substituted hydroxyurea (13) showed the most potent inhibitory activities against the enzyme.     

Structure-activity relationships of new N-acylanthranilic acid derivatives as plasminogen activator inhibitor-1 inhibitors

Novel anthranilic acid derivatives having substituted N-acyl side chains were designed and synthesized for evaluation as plasminogen activator inhibitor-1 (PAI-1) inhibitors. Compounds with a 4-diphenylmethyl-1-piperazinyl moiety on the acyl side chains in general exhibited potent in vitro PAI-1 inhibitory activity and good pharmacokinetic profiles after oral administration in rats. Compound 16f (TM5275) was identified as a promising candidate for further pharmacological evaluation.     

Synthesis of certain 2-substituted-1H-benzimidazole derivatives as antimicrobial and cytotoxic agents

A series of 2-substituted-1H-benzimidazole derivatives were synthesized and evaluated for antimicrobial, antifungal and cytotoxic activities. The results showed that all tested compounds showed potent antimicrobial activity against some species of Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Salmonella typhi) and fungi (Candida albicans) with minimum inhibitory concentrations (MICs) lower than 0.016 μg/mL. In contrast, all tested compounds were inactive against Staphylococcus aureus (Gram-positive bacterium). The final targets were also tested for their antitumor activity in vitro on cervical carcinoma (HeLa) cell line. Eight of the test compounds displayed more potent cytotoxic effect than doxorubicin at nanomolar concentrations. Compounds 2c and 3c exerted the strongest cytoyoxic effect with IC(50) 15 and 13 nM, respectively.     

Alpha-glucosidase inhibitors with a 4,5,6,7-tetrachlorophthalimide skeleton pendanted with a cycloalkyl or dicarba-closo-dodecaborane group.

Previous studies of alpha-glucosidase inhibitors derived from thalidomide revealed that 4,5,6,7-tetrachloro-N-alkylphthalimide derivatives are superior lead compounds. Structure-activity relationship studies indicated that a hydrophobic group at the N(2) position is mandatory for potent activity. Accordingly, we have designed and synthesized some 4,5,6,7-tetrachloro-N-cycloalkylphthalimide and 4,5,6,7-tetrachloro-N-dicarba-closo-dodecaborane derivatives. The prepared compounds exhibited potent alpha-glucosidase-inhibitory activity. Among them, 4,5,6,7-tetrachloro-N-cycloheptylphthalimide (9) showed the most potent activity, being approximately 30 times more active than the classical inhibitor, 1-deoxynojirimycin (1).     

Synthesis and pharmacological evaluation of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel antihypertensive agents

A series of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and their bradycardic activities were evaluated in isolated guinea pig right atria. Structure-activity relationship studies revealed that the introduction of an appropriate substituent and its position on the 1,2,3,4-tetrahydroisoquinoline ring are essential for potent in vitro activity. Furthermore, the tether between the piperidyl moiety and the terminal aromatic ring is important for potent antihypertensive activity. Oral administration of 6-fluoro-1-isopropyl-2-{[1-(2-phenylethyl)piperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline (3b) to spontaneously hypertensive rats (SHR) elicited antihypertensive effects without inducing reflex tachycardia, which is often caused by traditional L-type Ca2? channel blockers.     

Identification of novel alpha-glucosidase inhibitors by screening libraries based on N- [4-(benzyloxy) benzoyl] alanine derivatives

A library of 72 compounds related to N- [4-(benzyloxy) benzoyl]alanine (I) was synthesized, prepared and screened for alpha-glucosidase inhibitory activity. Four compounds showed potent inhibition, six compounds moderate inhibition, and 16 were weak inhibitors. One compound, N- [4-(benzyloxy) benzoyl] serine, was found to be a potent inhibitor of alpha-glucosidase with 100% inhibition at 1 micro M. This inhibitor was at least five times more potent than the lead compound I.     

Synthesis of some pseudo-peptide analogs of thiol proteinase inhibitors

Some pseudo-peptide analogs of thiol proteinase inhibitors were synthesized by a conventional solution method. Among them, Suc-Ala-Val-Val-Ala-psi-(CH2-NH)-Ala-pNA (peptide 1) and Suc-Ala-Val-Val-psi-(CH2-NH)-Ala-Ala-pNA (peptide 2) showed a stronger inhibitory activity compared with parent peptide such as Suc-Ala-Val-Val-Ala-Ala-pNA. In particular, peptide 2 was about 10-fold as active as the parent peptide (IC50 = 8 microM). Inserting psi-(CH2-NH) possibly makes the inhibitor less susceptible to papain and, as a result, produces more potent inhibition.     

Synthesis and antitumor activity of N1-acetylamino-(5-alkyl/aryl-1,3,4-thiadiazole-2-y1)-5-fluorouracil derivatives

A new series of N1-acetylamino-(5-alkyl/aryl- 1,3,4-thiadiazole-2-y1)-5-fluorouracil derivatives were designed and synthesized.These compounds have not been reported in literature,and their structure chemical were confirmed by IR,1H NMR and MS (HRMS).The results of antitumor inhibitory activity test showed that some compounds possess more potent antitumor inhibitory activity than 5-fluorouracil.     

Synthesis and CDK2 kinase inhibitory activity of 7/7′-azaindirubin derivatives

A series of novel 7′-azaindirubin (1a-g) and 7-azaindirubin (2a, 2c, 2e and 2f) derivatives were designed and synthesized. Their structures were characterized by 1H NMR and MS spectroscopy as well as by elemental analysis. Their inhibitory properties against CDK2/cylinA were evaluated in vitro. In contrast to indirubin, some of the described azaindirubins emerged as potent inhibitors of CDK2/cylinA and compound 2b had more potent activity. Biological tests also showed that nitrogen atom at 7-position of azaindirubin was more beneficial to enhance the kinase inhibitory activity.