Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere

We designed and synthesized a new class of peptidomimetic human immunodeficiency virus protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl isostere as the active moiety. From a structure-activity relationship study of HIV-1 protease inhibition, enzyme selectivity for other aspartyl proteases, the antiviral activity and pharmacokinetics in rats, 24c (KNI-227) and 24d (KNI-272, our first clinical candidate) were found to be selective and orally potent HIV protease inhibitors. Moreover, an improvement of the pharmacokinetic features of KNI-272 provided two long-lasting and highly bioavailable compounds (24g: JE-2178, 24h: JE-2179).     

KNI-102, a novel tripeptide HIV protease inhibitor containing allophenylnorstatine as a transition-state mimic.

HIV-1 protease inhibitors containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid]-Pro (syn diastereomer) as a transition-state mimic were established to be potent and highly selective. Z-Asn-Apns-Pro-NHBut (KNI-102) is the only tripeptide exhibiting substantial anti-HIV activity and may be of minimum size for potent, selective inhibition of HIV protease. Ready availability due to its simple chemical structure and stability should make it valuable for studies of the development of metabolically stable anti-AIDS drugs.     

Asymmetric synthesis of 3-amino-2-hydroxy-4-phenylbutanoate

Asymmetric synthesis of 3-amino-2-hydroxy-4-phenylbutanoate, a key component of the natural product bestatin and HIV protease inhibitors of KNI-272 and R-87366, has been achieved from the stereoselective aldimine coupling reaction between 3-phenyl-2-aminopropanenitrile and (Z)-α-methoxy trimethylsilyl ketene acetal in the presence of Lewis acids.     

KNI-272, a highly selective and potent peptidic HIV protease inhibitor

Kynostatin {KNI-272; systematic name: 3-[3-benzyl-2-hydroxy-9-(isoquinolin-5-yl­oxy)-6-methyl­sulfanyl­methyl-5,8-dioxo-4,7-di­aza­nonanoyl]-N-tert-butyl-1,3-thia­zolane-4-carbox­amide}, a highly selective and potent HIV protease inhibitor containing allo­phenyl­norstatin [(2S,3S)-3-amino-2-hydroxy-4-phenyl­butyric acid], has been crystallized as the hydrate, C₃₃H₄₁N₅O₆S₂·0.803H₂O, from aqueous hexyl­ene glycol. The observed disorder of the phenyl group in the structure is related to the mode of hydration. The backbone conformation of the mol­ecule is twisted and the overall conformation of the free inhibitor is similar to that observed in its complex with HIV protease.     

Synthesis of Novel 3-(5-(Alkyl/arylthio)-1,3,4-Oxadiazol-2-yl)-8-Phenylquinolin-4(1H)-One Derivatives as Anti-HIV Agents

Novel quinolone derivatives featuring an 1,3,4-oxadiazole ring as a metal-chelating component and a benzyl group base on HIV-1 integrase inhibitors pharmacophore were designed and synthesized. An antiviral assay revealed that most analogues inhibited HIV-1 replication in the cell culture. Our results showed that compounds bearing small alkyl groups as R group were inactive in anti-HIV-1 assay, whereas compounds possessing benzyl or substituted benzyl at the same position showed good anti-HIV activity with the range of 20–57% at 100 μM concentration. Among them, 3-(5-((2-fluorobenzyl)thio)-1,3,4-oxadiazol-2-yl)-8-phenylquinolin-4-(1H)-one (compound 13) showed reasonable cell-based antiviral activity (EC₅₀ = 50 μM) with no considerable cytotoxicity (CC₅₀ > 100 μM) in the cell viability assay, suggesting that it may be amenable to further development for identifying new anti-HIV-1 agents. Docking studies using the later crystallographic data available for PFV integrase corroborate favorable binding to the active site of HIV integrase, providing a basis for the design of more potent analogues.     

An efficient procedure for the preparation of (1S,3R)- and (1S,3S)-1-amino-3-(hydroxymethyl)cyclopentanes

Enantiomerically pure (1S,3S)- and (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentanes have been efficiently synthesized from L-aspartic acid. The title compounds are isosteres of ribose and may be used to construct nucleoside analogs with important antiviral and antineoplastic activities as demonstrated by a concise total synthesis of (+)-4'-deoxycarbapentostatin nucleoside.     

A novel method for the synthesis of 9-[[2-hydroxy-1-(aminomethyl)ethoxy]methyl]guanine - a potential antiviral agent

9-[[2-Hydroxy-1-(aminomethyl)ethoxy]methyl]guanine (1a), an amino analogue of 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine (I) which is a potent antiviral agent, has been synthesized $\text{via}$ a multistep-synthesis.     

Optically active antifungal azoles. VIII. Synthesis and antifungal activity of 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]- 3-(4-substituted phenyl)-2(1H,3H)-imidazolones and 2-imidazolidinones

New optically active antifungal azoles, 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl ]-3-(4- substituted phenyl)-2(1H,3H)-imidazolones (1,2) and 2-imidazolidinones (3,4), were prepared in a stereocontrolled manner from (1S)-1-[(2R)-2-(2,4- difluoro- and 2-fluorophenyl)-2-oxiranyl]ethanols (15, 16). Compounds 1-4 showed potent antifungal activity against Candida albicans in vitro and in vivo, as well as a broad antifungal spectrum for various fungi in vitro. Furthermore, the imidazolidinones, 3b--e and 4d, e, were found to exert extremely strong growth-inhibitory activity against Aspergillus fumigatus.     

Orally active GPIIb/IIIa antagonists: synthesis and biological activities of masked amidines as prodrugs of 2-[(3S)-4

To improve the in vivo potency of the potent GPIIb/IIIa antagonist 2-[(3S)-4-[(2S)-2-(4-amidinobenzoylamino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyljacetic acid (4), the amidino group was converted to an oxadiazole ring, thiadiazole ring or substituted amidoxime group. These groups were expected to be metabolized to an amidino group in vivo. The compounds synthesized were evaluated for their potency to inhibit the ex vivo adenosine 5'-diphosphate (ADP)-induced aggregation of guinea pig platelets. Among the compounds examined, the methoxycarbonyloxyamidine 8a exhibited the most potent ex vivo inhibitory activity with a fast onset and prolonged duration of action after oral administration.     

Synthesis and biological activities of optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl 5-(4,6-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dim ethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate dihydrochloride (NIP-101).

Six optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl 5-(4,6-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate dihydrochloride (NIP-101, 1.2HCl.2H2O), a potent calcium antagonist, were successfully prepared by using optically active (2R,4R)-(-)- and (2S,4S)-(+)-2,4-pentanediols, and cis-2,4-pentanediol and optically active (S)-(+)-2-methoxy-2-phenylethanol. Their proton nuclear magnetic resonance investigations demonstrate that the 1,3,2-dioxaphosphorinane group is conformationally constrained around the C-P bond. Calcium-antagonistic and hypotensive activities of the optical isomers were examined and found to depend mainly on the absolute configuration at a stereogenic center in the 1,4-dihydropyridine ring rather than the configuration of the 1,3,2-dioxaphosphorinane moiety.     

A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones: application to the asymmetric syntheses of neurokinin substance P receptor antagonist (-)-L-733,061 and (-)-deoxocassine

A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones based on the regio- and diastereoselective reductive alkylation of (S)-3-benzyloxyglutarimide 7 is described. This method opens an entrance to chiral nonracemic substituted 3-piperidinols. The versatility of the method is illustrated by the asymmetric syntheses of neurokinin substance P receptor antagonist L-733,061 (ent-1), (-)-deoxocassine (4), and an inhibitor of HIV proteases (5a).     

Synthesis of 9-(2,3-dihydroxy-1-propoxymethyl)guanine - a new potential antiviral agent

Coupling of tris(trimethylsilyl)guanine (4) with 1,2-di-$\text{O}$-acetyl-3-$\text{O}$chloromethyl glycerol (3), followed by removal of the protecting groups afforded 9-(2,3-dihydroxy-1-propoxy)guanine (1). Compound 1 exhibited potent antiviral activity.     

Anti‐AIDS active polyrotaxane‐AZT conjugates with bioactive bulky stoppers and their nanoparticles

New anti‐HIV active agents, polyrotaxane‐AZT conjugates with various bioactive bulky stoppers such as 3′‐azido‐3′‐deoxythymidine (AZT) and tocopherol and their nanoparticles were synthesized and characterized. The degree of AZT substitution of the conjugates was calculated from ELEM . ANAL and ranged from 1.8 to 5.9, respectively. The in vitro antiviral activity of these conjugates was determined and used to evaluate their potential applications in anti‐AIDS drugs. The in vitro anti‐HIV activities indicate that the synthesized polyrotaxane‐AZT conjugates and their nanoparticles against HIV‐1 and HIV‐2 strains were more potent inhibitors than free AZT, with reduced cytotoxicities against uninfected MT‐4 cells. The effect of the conjugates against HIV‐1 and HIV‐2 strains increased with decreasing particle size. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis and pharmacological activity of 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4- pyrrolidinyl]benzamide (TKS159) and its optical isomers

Of 4-amino-5-chloro-2-methoxy-N-(1-ethyl-2-hydroxymethyl-4- pyrrolidinyl)benzamide, four optical isomers, (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, were prepared from optically active 4-amino-1-ethyl-2-hydroxymethylpyrrolidine di-p-toluenesulfonate [(2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, respectively]. The requisites, (2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, were prepared from a commercially available trans-4-hydroxy-L-proline. The absolute configurations of (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27 were spectroscopically determined. Of the benzamide derivatives, four optical isomers, (2S,4S)-1, (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, showed a relatively potent affinity for 5-hydroxytryptamine 4 (5-HT4) receptors in a radioligand binding assay ([3H]GR113808). The activities of 25-27 were less effective than that of 1 for the gastric emptying of a phenol red semisolid meal in rats. All this suggests that the most potent of the isomers was 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2- hydroxymethyl-4-pyrrolidinyl]benzamide (1).     

Structures and related properties of AgX bearing 3,3'-thiobispyridine (X- = NO3-, BF4-, CLO4-, and PF6-

Infinite molecular helices [Ag(3,3'-Py2S)]X (3,3'-Py2S = 3,3'-thiobispyridine; X- = BF4-, ClO4-, and PF6-) have been rationally constructed or induced. Crystallographic characterization (X- = BF-, monoclinic P2(1)/n, a = 8.946(3) A, b = 14.130(2) A, c = 10.124(2) A, beta = 107.83(2) degrees, V = 1218.3(5) A3, Z = 4, R = 0.0351; X- = ClO4-, monoclinic P2(1)/n, a = 8.884(1) A, b = 14.305(3) A, c = 10.110(1) A, beta = 106.78(1) degrees, V = 1230.1(3) A3, Z = 4, R = 0.0417; X- = PF6-, monoclinic P2(1)/c, a = 10.959(2) A, b = 9.808(2) A, c = 14.065(3) A, beta = 112.03(2) degrees, V = 1401.4(5) A3, Z = 4, R = 0.0442) reveals that the skeletal structure is an oblong cylindrical cationic helix consisting of alternating Ag(I) and 3,3'-Py2S species and that its counteranions are pinched in two columns inside each helix. The formation of the helical coordination polymer appears to be primarily associated with a suitable combination of the skewed conformer of 3,3'-Py2S and the potential linear geometry of the N-Ag(I)-N bond. However, the framework of the nitrate analogue [Ag(3,3'-Py2S)NO3] (monoclinic P2(1)/c, a = 8.177(2) A, b = 10.291(1) A, c = 14.771(2) A, beta = 102.19(1) degrees, V = 1214.9(4) A3, Z = 4, R = 0.0300) is a two-dimensional network consisting of an 18-membered ring unit, where each 3,3'-Py2S acts as a N,N',S- tridentate ligand connecting three tetrahedral silver(I) ions with the monodentate nitrate weakly bonded to the silver (Ag.O = 2.65(1) A) rather than acting as a counteranion. The anion exchange of [Ag(3,3'-Py2S)NO3] with BF4-, ClO4-, or PF6- has been accomplished in aqueous media. The two-dimensional networks are easily converted into the helices via the anion exchange, but the reverse anion exchange proceeds slightly. Thermal analyses indicate a relationship between the thermal stabilities and the structural properties.     

Syntheses and structures of chalcogen–molybdenum clusters; [Mo3XSe6{S2P(OEt)2}3]Cl, [Mo3X(SeS)3{S2P(OEt)2}3]I and [Mo3 XSe3{S2P(OEt)2}4(py)] (X=0.65S+0.35Se,py= C5H5N)

The trinuclear Mo cluster [Mo3(3–X)(2–Se2)3{S2P-(OEt)2}3]Cl (X=0.65S+0.35Se) (1) has been synthesised by reacting MoCl3·3H2O with ZnSe and [Me4N][S2P(OEt)2] in an EtOH/HCl medium. Reduction of (1) by Ph3P in the presence of [Me4N]-[S2P(OEt)2] and pyridine gave [Mo3(3–X)(2–Se)3 {S2P(OEt)2}4(py)] (X=0.65S+0.35Se, py=C5H5N) (2). Complex (2) was, in turn, converted into [Mo3(3–X)(2–SeS)3{S2P(OEt)2}3]I (X=0.65S+0.35Se) (3) by treatment with H2S and I2. The structures of complexes (1), (2) and (3) were established by X-ray crystallography.     

Synthesis and modeling study of (2S,5R,6R)- and (2S,5R,6S)-6-hydroxy- 8-(1-decynyl)-benzolactam-V8 as protein kinase C modulators

[structures: see text] Both (2S,5R,6R)- and (2S,5R,6S)-6-hydroxy-8-(1-decynyl)benzolactam-V8 were designed and synthesized as PKC modulators. Biological assays reveal the (6R)-ligand to be 20-fold more potent than its (6S)-counterpart in binding to PKC alpha.     

Synthesis and anti-HIV activity of 3-alkylamido-3-deoxy-betulinic acid derivatives

3-Alkylamido-3-deoxy-betulinic acids were synthesized and evaluated for anti-HIV activity as part of the structure-activity relationship study of the potent anti-HIV agent 3-O-(3',3'-dimethyl)-succinyl-betulinic acid (DSB) (2). 3Alpha-diglycorylamide-3-deoxy-betulinic acid demonstrated relatively potent anti-HIV activity (EC50 0.24 microm, TI 728). However, replacing the ester group at C-3 in 2 and its analogues with an amido group yielded inactive or much less potent compounds against HIV replication, indicating that the ester group at C-3 in 2-4 is essential for potent anti-HIV activity.