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A core 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-one scaffold is elaborated at C-3(Me) by base-mediated aldol condensation to give new 3-alkenyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-ones, which are masked forms related to the acylpyridone natural products.

O -Alkyl and O -aryl carbamate derivatives of the antimalarial drug primaquine were synthesised as potential prodrugs that prevent oxidative deamination to the inactive metabolite carboxyprimaquine. Both O -alkyl and O -aryl carbamates undergo hydrolysis in alkaline and pH 7.4 phosphate buffers to the parent drug, with O -aryl carbamates being ca. 10 6 –10 10 more reactive than their O -alkyl counterparts. In human plasma O -alkyl carbamates were stable, whereas in contrast their O -aryl counterparts rapidly released the corresponding phenol product, with primaquine being released only slowly over longer incubation periods. Activation of the O -aryl carbamates in human plasma appears to be catalysed by butyrylcholinesterase (BuChE), which leads to carbamoylation of the catalytic serine of the enzyme followed by subsequent slow enzyme reactivation and release of parent drug. Most of the O -aryl and O -alkyl carbamates are activated in rat liver homogenates with half-lives ranging from 9 to 15 h, while the 4-nitrophenyl carbamate was hydrolysed too rapidly to determine an accurate rate constant. Antimalarial activity was studied using a model consisting of Plasmodium berghei , Balb C mice and Anopheles stephensi mosquitoes. When compared to controls, ethyl and n -hexyl carbamates were able to significantly reduce the percentage of infected mosquitos as well as the mean number of oocysts per infected mosquito, thus indicating that O -alkyl carbamates of primaquine have the potential to be developed as transmission-blocking antimalarial agents.

The reactivity of 6-quinolinyl and 8-quinolinyl N,N-dimethylcarbamates was examined in several aqueous basic media. A quadratic dependence was observed for the constant rates upon hydroxide concentration for both compounds, which is a typical behaviour of a mechanism involving a base-catalysed deprotonation of the tetrahedral intermediate with the formation of a dianion at high concentrations of hydroxide ion, while at lower concentrations a specific-base catalysed addition–elimination mechanism seems to be predominant. The reactivity of 8-quinolinyl N,N-dimethylcarbamate was also studied in several amine buffers, showing specific base catalysis. The reactivity of 6-quinolinyl N,N-dimethylcarbamate was studied in H2O and in D2O and the solvent isotope effect supports the proposal of a mechanism involving a specific-base hydrolysis. All results confirm the existence of a mechanism with a rate determining step involving the substrate anion and a second mole of hydroxide ion. This mechanism was so far unknown for carbamate reactivity, being only known to occur with amides. Copyright © 2011 John Wiley & Sons, Ltd.

S-Alkylation of an N-protected cysteine ester with a range of ω-iodoalkyl heterocycles affords 11 novel non-proteinogenic heterocyclic amino acids having a sulfur atom in the backboneheterocycle linker.

A core isoxazolo[4,3-c]pyridin-4-one scaffold is prepared and elaborated at C-3(Me) and C-7 as a masked building block for 3-acylpyridin-2-ones related to the acylpyridone natural products.

Dipolar cycloadditions of azomethine imines, formed in situ from aldehydes and N1-alkyl-N2-acylhydrazines, with electron-deficient dipolarophiles produce pyrazolidines: mono-substituted dipolarophiles afford principally 4-substituted pyrazolidines.

Substituted secondary N-thiazolylcarbamate esters and some tertiary N-methyl, N-thiazolyl carbamate esters have been synthesised and the mechanism of the OH- catalysed hydrolyses investigated. These proved to be E1cB and BAc2 respectively, and this behaviour was compared with that of other carbamates.

Carbamate and ester derivatives of the 1,1-dioxobenzo[b]thiophen-2-ylmethyloxycarbonyl (Bsmoc) scaffold react readily with thiols via a Michael addition at rates not significantly affected by the nature of the carboxylic or carbamic acid leaving group. These Michael acceptors are irreversible inhibitors of the cysteine proteases papain and human liver cathepsin B, displaying first-order kinetics with respect to inhibitor concentration. In contrast, none of the Bsmoc derivatives inhibited porcine pancreatic elastase, a serine protease. (C) 2006 Elsevier Ltd. All rights reserved.

Novel N-Mannich base-type derivatives of the antimalarial drug amodiaquine were synthesised by reaction with tertiary N-chloromethylamides. With the exception of the derivative of ethyl hippurate, all the so-formed (1-amidomethyl-1H-quinolin-4-ylidene)arylamines displayed high chemical and enzymatic stability. These compounds displayed antimalarial activity against the multi-drug resistant Plasmodium falciparum strain Dd2 (IC50 values 15–31 nM) and demonstrated no significant loss in activity compared to amodiaquine (IC50 30 nM).

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N α -protected amino acids, (ii) removal of the N α -protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1 H -imidazo[2,1- a ]isoindole-2,5(3 H ,9b H )-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1 H -imidazo[2,1- a ]isoindole-2,5(3 H ,9b H )-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly ( t 1/2 5–30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.

Tertiary benzamides are oxidized by the 5,10,15,20-tetraphenylporphyrinatoiron(III) chloride-(BuOOH)-O-t system at the alpha-position of the N-alkyl groups. The major products are N-acylamides, although small amounts of secondary amides, the products of dealkylation, are also formed. Plots of initial rate versus initial substrate concentration for these reactions are curved, suggesting formation of an oxidant-substrate complex. The reaction rates are almost insensitive to the substituent in the benzamide moiety, but there is a kinetic deuterium isotope effect of 5.6 for the reaction of the N, N-(CH3)(2) and N, N-(CD3)(2) compounds. Comparison of the reaction products from N-alkyl-N-methylbenzamides reveals that, for all compounds studied except N-cyclopropyl-N-methylbenzamide, oxidation of the alkyl group is preferred, strongly so (by a factor of ca. 8) for N-allyl-N-methylbenzamide. In contrast to microsomal oxidation, there is no steric hindrance to oxidation of an isopropyl group. Thus, we propose that these reactions proceed via hydrogen atom abstraction to form an alpha-carbon-centred radical and we attribute the observed diminished reactivity of the N-cyclopropyl group to its known reluctance to form a cyclopropyl radical. Oxidation of N-methyl-N-(2,2,3,3-tetramethylcyclopropyl)methylbenzamide provides preliminary evidence for rearrangement of an intermediate radical. While it remains unclear how these reactions proceed directly to the N-acyl products, we have established that N- hydroxymethyl, N-alkoxymethyl and N-alkylperoxymethyl intermediates are not involved.

Aminocarbonyloxymethyl esters 3 based on (S)-amino acid carriers were synthesised and evaluated as potential prodrugs of carboxylic acid agents. In addition, the compounds were evaluated as topical prodrugs with the aim of improving the dermal delivery of two non-steroidal anti-inflammatory agents: naproxen and flufenamic acid. The lipophilicities of these compounds were determined and their hydrolyses in aqueous solutions and in human plasma were examined. Compounds 3 containing a secondary carbamate group were hydrolysed at pH 7.4 by two different routes: (i) direct nucleophilic attack at the ester carbonyl carbon leading to the release of the parent carboxylic acid and (ii) intramolecular rearrangement involving an O--N acyl migration, leading to the formation of the corresponding amide. The rearrangement pathway is highly dependent on the size of the carboxylic acid and amino acid substituents, being eliminated when the amino acid is valine or leucine. In contrast, compounds 3 decomposed in plasma exclusively through ester hydrolysis, most releasing the parent carboxylic acid quantitatively with half-lives shorter than 5 min. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. All prodrugs evaluated exhibited a lower flux than the corresponding parent carboxylic acid. The poor skin permeation observed for compounds 3 is most probably due to their low aqueous solubility and high partition coefficient. (C) 2002 Elsevier Science Ltd. All rights reserved.

N -(2-iodoethyl) and N -(3-iodopropyl)pyrimidines and purines undergo stereoselective conjugate radical addition with an optically active oxazolidinone acceptor to give syn -adducts that can be converted into amino acids carrying pyrimidine and purine (nucleobase) side chains.

4,5-Dihydroimidazoles undergo an N-alkylation and 1,3-dipolar cycloaddition cascade with unsaturated α-bromoketones, with subsequent eliminative ring-opening, recyclisation and tautomerisation to form unexpected hexahydropyrrolo[1,2,3-de]quinoxalines.

The kinetics of the hydrolyses of secondary and tertiary N-amidomethylsulfonamides were studied at 50 degreesC. Both types of N-amidomethylsulfonamide hydrolyse through acid- and base-catalysed processes, as indicated by the pH-rate profiles. The order of reactivity for the acid-catalysed pathway implies a mechanism involving protonation of the amide followed by expulsion of a neutral amide and formation of a sulfonyliminium ion. In the base-catalysed region, compound 5c, which is substituted at both amide and sulfonamide nitrogen atoms, hydrolyses by nucleophilic attack of hydroxide ion at the amide carbonyl carbon atom to form benzoic acid and a sulfonamide. In contrast, compound 5b, which contains a sulfonamide NH group, hydrolyses to benzamide and sulfonamide products by an E1cb(rev) mechanism involving ionisation of the sulfonamide. Compound 5a, which contains an amide NH, also hydrolyses to sulfonamide and amide products, probably by an E2 mechanism.

An orthogonally protected 3-(1-aminoalkyl)isoxazole-4-carboxylic acid has been prepared by 1,3-dipolar cycloaddition of a suitably protected α-aminonitrile oxide with an enaminoester dipolarophile; this protected amino acid has been deprotected and coupled independently at either the C- or N-terminus to produce pseudopeptide segments as peptide mimetics that contain a cis -amide bond replacement.

A series of 3-acyloxymethyloxycarbonyl-1-aryl-3-methyltriazenes 5 was synthesised by the sequential reaction of 1-aryl-3-methyltriazenes with (i) chloromethyl chloroformate, (ii) NaI in dry acetone, and (iii) either the silver carboxylate or the carboxylic acids in the presence of silver carbonate. The hydrolysis of these compounds was studied in pH 7.7 isotonic phosphate buffer and in human plasma. Triazene acyloxycarbamates demonstrated their ability to act as substrates for plasma enzymes. For compound 5f, a pH-rate profile was obtained which showed the hydrolysis to involve acid-base catalysis. The reaction is also buffer catalysed. Thus, at pH 7.7, pH-independent, base-catalysed and buffer-catalysed processes all contribute to the hydrolysis reaction. The sensitivity of the hydrolysis reaction to various structural parameters in the substrates indicates that hydrolysis occurs at the ester rather than the carbamate functionality. In plasma, the rates of hydrolysis correlate with partition coefficients, the most lipophilic compounds being the most stable. An aspirin derivative suffers two consecutive enzymatic reactions, the scission of the aspirin acetyl group being followed by the scission of the acyloxy ester group. These results indicate that triazene acyloxymethyl carbamates are prodrugs of the antitumour monomethyltriazenes. They combine chemical stability with a rapid enzymatic hydrolysis, and are consequently good candidates for further prodrug development. Moreover, this type of derivative allowed the synthesis of mutual prodrugs, associating the antitumour monomethyltriazenes with anti-inflammatory NSAIDs as well as with the anticancer agent butyric acid.

Tertiary sulfonamidomethyl esters of benzylpenicillin ( 4 ) were synthesised and evaluated as a new class of potential prodrugs for β-lactam antibiotics. Their hydrolysis in aqueous buffers was studied by HPLC and reveal a U-shaped pH–rate profile with a pH-independent process extending from ca. pH 2 to ca. pH 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Benzylpenicillin and the corresponding sulfonamide are the ultimate products detected and isolated, indicating that β-lactam ring opening is much slower than ester hydrolysis. As expected from the high reactivity, benzylpenicillin esters ( 4 ) displayed similar in vitro antibacterial activity to benzylpenicillin itself. Compared to the benzylpenicillin derivatives, sulfonamidomethyl esters of benzoic, clofibric and valproic acids display a much higher stability, giving rise to a Bronsted β lg value of −0.96 and suggesting that tertiary sulfonamidomethyl esters may be useful prodrugs for carboxylic acid drugs with p K a >4.

Purpose. Dipeptide derivatives of primaquine (PQ) with reduced oxidative deamination to the inactive metabolite carboxypnmaquine were synthesized and evaluated as a novel class of transmission-blocking antimalarials.

Kinetics of acid hydrolysis of 1-methyl-1-nitroso-3-p-tolylsulfonylguanidine 2 and of two 1-methyl-1-nitroso-3-benzoylguanidines (4-unsubstituted and 4-chloro) 5 and 6 have been studied. For the acid hydrolysis of 1-methyl-1-nitroso-3-p-tolylsulfonylguanidine 2, the absence of catalysis by thiocyanate ion, and the value of the kinetic solvent isotope effect indicate that either a rate determining proton transfer followed by fast denitrosation or a concerted pathway is involved in the mechanism. In the case of the acid hydrolysis of 1-methyl-1-nitroso-3-benzoylguanidines 5 and 6 it was observed that the protonated form decomposes via two parallel pathways. One involves a slow nucleophilic attack concerted with an intramolecular proton transfer, and the other a slow concerted denitrosation, where a second proton transfer and NO+ expulsion are simultaneous.

Purpose. The synthesis of chemically stable triazene prodrugs capable of hydrolysing under physiological conditions to liberate cytotoxic monomethyltriazene alkylating agents.

Purpose. Novel tertiary amidomethyl esters were synthesized and evaluated as potential prodrugs of carboxylic acid agents.

Purpose. O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs. Methods. Their hydrolysis in aqueous buffers containing 20 % (v/v) of acetonitrile was investigated by HPLC. Results. A U-shaped pH-rate profile was seen with a pH-independent process extending from pH ca. 2 to pH ca. 10. This pathway is characterised by kinetic data that are consistent with a uni-molecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Penicillin G and the corresponding amide are the ultimate products detected and isolated, indicating that β-lactam ring opening is much slower than ester hydrolysis. The O-(N-alkylamido)methyl esters of penicillin G displayed similar in vitro antibacterial activity to penicillin G itself. Conclusions. Compared to the penicillin G derivatives, the much higher stability of the O-(N-methylbenzamido)methyl benzoate, acetate and valproate esters (which gave rise to a Bronsted βlg value of ca. -1) suggests that tertiary N-acyloxymethylamides may be useful prodrugs for carboxylic acid drugs with pKa >4.

Title compounds (VI) and (XVI) are synthesized starting from esters (I) or (XII), resp., via dipolar cycloaddition of nitrile oxides derived from the latter in situ with enamino-ester (III).

The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors.

N-Alkyl-N-chloromethylamides 2, prepared from secondary amides, paraformaldehyde and chlorotrimethylsilane, react readily with carboxylate anions to generate the corresponding tertiary N-acyloxymethylamides 3 in good yield; the latter give rise to the parent carboxylic acids in aqueous media at pH 7.4 and 37 °C with half-lives between ca. 1 min and 42 h.

Molecular modeling studies carried out with experimental DNA models with the sequence d[AG(3)(T(2)AG(3))(3)] suggest that the introduction of a net positive charge onto the side chain of a series of fluorenone carboxamides can improve G-quadruplex binding. The terminal morpholino moiety was replaced with a novel N-methylmorpholinium cation starting from two 4-carboxamide compounds. A different substitution on the fluorenone ring was also investigated and submitted to the same quaternarization process. All compounds were analyzed for their DNA binding properties by competition dialysis methods. In vitro antiproliferative tests were carried out against two different tumor cell lines. Docking experiments were conducted by including all four known human repeat unit G-quadruplex DNA sequences (27 experimentally determined conformations) against the most active fluorenone derivatives. The results of theoretical, biophysical, and in vitro experiments indicate two novel derivatives as lead compounds for the development of a new generation of G-quadruplex ligands with greater potency and selectivity.

We report here a simple entry into naphtho[2,3-d]isoxazole-4,9-dione system containing a EWG in position 3 using the readily available 2,3-dichloro-1,4-naphthoquinone and nitromethyl derivatives in the presence of base. Antifungal activity of synthesised naphthoquinones was evaluated against ATCC and PYCC reference strains of Candida. The results suggest that the naphtho[2,3-d]isoxazole-4,9-dione scaffold has the potential to be developed into novel and safe therapeutic antifungal agents.

A catalytic method involving carbenoid insertion onto dihydroimidazoles is reported for the generation of dihydroimidazolium ylides, and their subsequent diastereoselective cycloaddition to form pyrrolo[1,2-a]imidazoles.

The fluorescent dihydropyrimido[1,2-a]quinoline chromophore of the pyoverdin siderophores has been synthesized by a biomimetic oxidative cyclization using an iodine(III) reagent, followed by elimination and dehydrogenation.

A series of 3-[alpha-(acylamino)acyl]-1-aryl-3-methyltriazenes 6a-l, potential cytotoxic triazene prodrugs, were synthesised by coupling 1-aryl-3-methyltriazenes to N-acylamino acids. Their hydrolysis was studied in isotonic pH 7.4 phosphate buffer and in human plasma, while hydrolysis of the derivative 6a was studied in more depth across a range of pH values. Prodrugs 6a-l hydrolyse by cleavage of the triazene acyl group to afford the corresponding monomethyltriazenes. Studies in human plasma demonstrate that acylation of the alpha-amino group of the amino acid carrier is an effective means of reducing the chemical reactivity of the alpha-aminoacyl derivatives while retaining a rapid rate of enzymatic hydrolysis. These derivatives displayed logP values that suggest they should be well absorbed through biological membranes.

A range of triazene derivatives were synthesized and investigated as prodrug candidates for melanocyte-directed enzyme prodrug therapy (MDEPT). The prodrugs contained a tyramine or dopamine promoiety required for tyrosinase activation and this was joined via a urea functional group to the cytotoxic triazene. The stability of each of the prodrugs in phosphate buffer, human plasma and in mushroom tyrosinase is discussed. The identification of the main peak formed after the tyrosinase reaction was attempted by LC-MS and the conversion of prodrug to the quinone was confirmed.

Sumatriptan is a potent and selective 5-HT(1B) and 5-HT(1D )agonist used in the symptomatic treatment of migraine; it shows poor oral bioavailability ascribed, in part, to its low lipophilicity. In an attempt to develop acyloxymethyl prodrugs of sumatriptan suitable for oral administration, we carried out the reaction of sumatriptan with chloromethyl esters. To our surprise, acyloxymethylation occurred preferentially at the indole nitrogen rather than at sulfonamide nitrogen, reflecting a difference either in product stability or in the nucleophilicities of the indole and sulfonamide anions. The hydrolysis of the corresponding N(1)-acyloxymethyl derivatives was studied in aqueous buffers and in human plasma, by HPLC. N(1)-Acyloxymethyl derivatives of sumatriptan are rapidly hydrolysed to the chemically stable N(1)-hydroxymethylsumatriptan at pH 1-13. Slow formation of the parent drug was observed only at high pH values. Hydrolysis of sumatriptan derivatives is slower in human plasma than in phosphate buffer and also generates N(1)-hydroxymethylsumatriptan rather than the parent drug. These results indicate that N(1)-acyloxymethyl derivatives of sumatriptan cannot be considered as true prodrugs of sumatriptan.

A series of 1,4-naphthoquinone derivatives diversely substituted at C-2, C-3, C-5 and C-8, prepared by reaction of amines, amino acids and alcohols with commercial 1,4-naphthoquinones, has been evaluated against papain and bovine spleen cathepsin B. These 1,4-naphthoquinone derivatives were found to be irreversible inhibitors for both cysteine proteases, with second-order rate constants, k(2), ranging from 0.67 to 35.4 M-1 s(-1) for papain, and from 0.54 to 8.03 M-1 s(-1) for cathepsin B. Some derivatives display a hyperbolic dependence of the first-order inactivation rate constant, k(obs) with the inhibitor concentration, indicative of a specific interaction process between enzyme and inhibitor. The chemical reactivity of the compounds towards cysteine as a model thiol is dependent on the naphthoquinone LUMO energy, whereas papain inactivation is not. The 1,4-naphthoquinone derivatives are inactive against the serine protease, porcine pancreatic elastase. (c) 2007 Elsevier Ltd. All rights reserved.

Aminocarbonyloxymethyl ester prodrugs are known to undergo rearrangement in aqueous solutions to form the corresponding N-acylamine side product via an O--N intramolecular acyl transfer from the carbamate conjugate base. Novel aminocarbonyloxymethyl esters of diclofenac and flufenamic acid containing amino acid amide carriers were synthesized and evaluated as potential prodrugs displaying less ability to undergo rearrangement. These compounds were prepared in reasonable yield by a four-step synthetic method that uses the appropriate N-Boc-protected amino acid N-hydroxysuccinimide ester and secondary amine and chloromethyl chloroformate as key reactants. Their reactivity in pH 7.4 buffer and 80% human plasma at 37 degrees C was assessed by RP-HPLC. The aminocarbonyloxymethyl esters containing a secondary carbamate group derived from amino acids such as glycine or phenylalanine were hydrolyzed quantitatively to the parent drug both in non-enzymatic and enzymatic conditions, with no rearrangement product being detected. The oral bioavailability in rats was determined for selected diclofenac derivatives. These derivatives displayed a bioavailability of 25 to 68% relative to that of diclofenac, probably due to their poor aqueous solubility and lipophilicity. These results suggest that further optimization of aminocarbonyloxymethyl esters as potential prodrugs for non-steroidal anti-inflammatory drugs require the use of amino acid carriers with ionizable groups to improve aqueous solubility.

A series of fluorenone-carboxamide compounds was analyzed with regard to DNA binding properties by UV spectroscopy and competition dialysis methods. The morpholino derivative 10 provided interesting results in terms of affinity and specificity toward the DNA G-tetraplex structures. Interactions against this target were evaluated by a comparative molecular modeling study in agreement with the experimental data, proposing a model for the rational design of new agents with potent and selective DNA tetraplex binding properties.

The presence of a leaving group at C- 4 of monobactams is usually considered to be a requirement for mechanism- based inhibition of human leukocyte elastase by these acylating agents. We report that second- order rate constants for the alkaline hydrolysis and elastase inactivation by N- carbamoyl monobactams are independent of the pK(a) of the leaving group at C- 4. Indeed, the effect exerted by these substituents is purely inductive: electron- withdrawing substituents at C- 4 of N- carbamoyl- 3,3- diethylmonobactams increase the rate of alkaline hydrolysis and elastase inactivation, with Hammett p(I) values of 3.4 and 2.5, respectively, which indicate the development of a negative charge in the transition- states. The difference in magnitude between these p(I) values is consistent with an earlier transition- state for the enzymatic reaction when compared with that for the chemical process. These results suggest that the rate- limiting step in elastase inactivation is the formation of the tetrahedral intermediate, and that beta- lactam ring- opening is not concerted with the departure of a leaving group from C- 4. Monobactam sulfones emerged as potent elastase inhibitors even when the ethyl groups at C- 3, required for interaction with the primary recognition site, are absent. For one such compound, a 1 : 1 enzyme - inhibitor complex involving porcine pancreatic elastase has been examined by X- ray crystallography and shown to result from serine acylation and sulfinate departure from the beta- lactam C-4.

Amino acids carrying aromatic carbo- and heterocycles in the side chain, such as naphthyl-, biphenyl- and pyridylalanines, have been prepared by alkylation of a glycine enolate with a haloalkyl carbocycle or heterocycle, with enantiomeric excess up to 87% using the ephedrine amide protocol.

N-Alkylation of 4,5-dihydroimidazoles with alkene-containing bromomethyl ketones and treatment of the so-formed 4,5-dihydroimidazolium ions with DBU gives rise to an intramolecular 1,3-dipolar cycloaddition reaction that affords (via a reaction cascade involving eliminative ring-opening, recyclisation and prototropic tautomerism) unexpected hexahydropyrrolo[1,2,3-de]quinoxaline products. Steric bulk in both the dihydroimidazole and the dipolarophile allows isolation of an imidazo[1,2-a]indole, the initial product of cycloaddition. When the bromomethyl ketone contains no other functionality, or when cycloaddition is inhibited due to steric constraints, the dihydroimidazolium ion undergoes ring-opening hydrolysis followed by recyclization of the exposed amino ketone to afford either 3-alkyl-1-formylpiperazine-2-ones or 3-aryl-1-formyl-1,4,5,6-tetrahydropyrazines.

The synthesis of a range of fluorinated heterocycles is described via a Lewis acid-mediated Prins-type cyclisation.

The synthesis of phosphonate derivatives of N-phenyl- and N-benzyl-gamma- and delta-sultams, and their application in the Wittig-Horner reaction with N-Boc-L-phenylalanine aldehyde to afford E- and Z-isomers, are described. These compounds were further processed to provide five dipeptide vinyl sultams, which were found to be inactive against papain at concentrations up to 50 microM. In contrast, vinyl sultams demonstrated weak activity against recombinant falcipain-2 and Plasmodium falciparum W2.

In contrast to peptide-based imidazolidin-4-ones, those synthesized from N-(alpha-aminoacyl) derivatives of the antimalarial drug, primaquine and ketones are unexpectedly stable in pH 7.4 at 37 degrees C. The kinetics of hydrolysis of primaquine-based imidazolidin-4-ones were investigated in the pH range 0.3-13.5 at 60 degrees C. The hydrolysis to the parent alpha-aminoacylprimaquine is characterized by sigmoidal-shaped pH-rate profiles, reflecting the spontaneous decomposition of both unionized and protonated (at N-1) forms of the imidazolidin-4-one. The kinetically determined pK(a) values are ca. 3.6-4.0, i.e., 4 pKa units lower than those of amino acid amides, thus implying that hydrolysis of imidazolidin-4-ones at pH 7.4 involves the unionized form. Reactivity of this form decreases with the steric crowding of the amino acid alpha-substituent. In contrast, the rate constant for the spontaneous decomposition of the unionized form increases sharply for imidazolidin-4-ones derived from cyclic ketones, an observation that can be explained by the I-strain (internal strain) effect. These results are consistent with a mechanism of hydrolysis involving an S(N)1-type unimolecular cleavage of the imidazolidin-4-one C2-N3 bond with departure of an amide-leaving group. The mechanism for the decomposition of the protonated imidazolidin-4-one is likely to involve an amide-carbonyl oxygen protonated species, followed by the C2-N3 bond scission, as supported by computational studies. The results herein presented suggest that imidazolidin-4-ones derived from simple N-alkyl alpha-aminoamides are too stable and therefore, may be useful as slow drug release prodrugs.

1-Aryl-3-aryloxymethyl-3-methyltriazenes hydrolyse to the corresponding anilines and phenols by specific-acid-catalysed, general-acid-catalysed and pH-independent mechanisms. All compounds studied exhibit specific- and general acid catalysis, though for 5a general acid catalysis was not observed below a pH of approximately 4, while for compounds 5e,f, such catalysis was absent above a pH of approximately 5. The pH-independent pathway is observed only for those compounds, 5d-f, that contain good aryloxy nucleo-fugic groups. The specific-acid-catalysed pathway is supported by a solvent deuterium isotope effect (SDIE) of 0.64, consistent with a mechanism involving protonation of the substrate followed by rate-determining unimolecular decomposition of the protonated species. The k(H+) values gave rise to a Hammett p value of -0.93, reflecting the competing effect of the substituents on the protonation of the substrate and the cleavage of the aryl ether. Correlation of k(H+) with the pK(a) of the phenol leaving group affords a beta(1g) of 0.3. Decomposition of the protonated intermediate proceeds via a triazenyliminium ion that can be trapped by methanol. The general-acid-catalysed process exhibits an SDIE of 1.43 and Hammett p values of 0.49, 0.84 and 1.0 for reactions catalysed by chloroacetic, formic and acetic acids, respectively. Correlation of k(A) with the pK(a) of the acid gave Bronsted a values that diminish from 0.6 for O-aryl systems that are poor nucleofuges (5a,b) to 0.2 for the best nucleofuge (5f), reflecting the different extents of proton transfer required to expel each phenol. Compounds containing powerful nucleofuges exhibit a pH-independent reaction that has an SDIE of 1.1, a Hammett p value of 3.4 and a Bronsted beta(1g) value of 1.4. These imply a mechanism involving displacement of the aryloxide leaving group to form a triazenyliminium ion intermediate that again was trapped as a methyl ether. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The pH-independent, acid-catalyzed and base-catalyzed hydrolyses of N-acyloxymethylazetidin-2-ones all occur at the ester function. The pH-independent hydrolysis involves rate-limiting alkyl C-O fission and formation of an exocyclic beta-lactam iminum ion. This iminium ion is then trapped by water at the exocyclic iminium carbon atom, rather than at the beta-lactam carbonyl carbon atom, to form the corresponding N-hydroxymethylazetidin-2-ones. Calculations carried out at the B3LYP/6-31+G(d) level of theory also support that nucleophilic attack by water takes place at the exocyclic carbon rather than at the beta-lactam carbonyl carbon of the iminium ion. The mechanism for the acid-catalyzed pathway involves a preequilibrium protonation, probably at the beta-lactam nitrogen, followed by rate-limiting alkyl C-O fission with formation of an exocyclic iminum ion. The base-catalyzed hydrolysis involves rate-limiting hydroxide attack at the ester carbonyl carbon. These results imply formation of a beta-lactam system containing a positively charged amide nitrogen atom that hydrolyzes via a pathway that preserves the beta-lactam structure in the product and provide further evidence that cleavage of the beta-lactam C-N bond is not as facile as is commonly imagined.

Several new 4,5-dihydroimidazoles (and the corresponding imidazolium salts) carrying heteroatom substituents at C-2 have been prepared from the corresponding tetrahydroimidazol-2-ones and/or -thiones.

A series of N-acyloxymethyl- and N-aminocarbonyloxymethyl derivatives of 2-azetidinones. 3, with different substituent patterns at the beta -lactam C-3 and C-4 positions, were designed as potential mechanism-based inhibitors for human leukocyte elastase and found to exhibit inhibitory potency and selectivity for the enzyme, (C) 2001 Elsevier Science Ltd. All rights reserved.

Tertiary N-acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides were synthesised and evaluated as novel classes of potential prodrugs of agents containing a secondary sulfonamide group. The chemical and plasma hydrolyses of the title compounds were studied by HPLC. Tertiary N-acyloxymethylsulfonamides are slowly and quantitatively hydrolysed to the parent sulfonamide in pH 7.4 phosphate buffer, with half-lives ranging from 20 h, for 7d, to 30 days, for 7g. Quantitative formation of the parent sulfonamide also occurs in human plasma, the half-lives being within 0.2–2.0 min for some substrates. The rapid rate of hydrolysis can be ascribed to plasma cholinesterase, as indicated by the complete inhibition observed at [eserine]=0.10 mM. These results suggest that tertiary N-acyloxymethylsulfonamides are potentially useful prodrugs for agents containing a secondary sulfonamide group, especially with pKa 7h Download : Download high-res image (22KB) Download : Download full-size image Scheme 1 . (i) ClCH2OCOCl/Et3N/CH2Cl2; (ii) NaI/acetone; (iii) 5 (sodium salt)/THF. –j do not liberate the parent sulfonamide either in aqueous buffers or in human plasma and thus appear to be unsuitable for development as sulfonamide prodrugs.

Phthalimidomethyl derivatives 1, encompassing a wide range of leaving group abilities, are rapidly hydrolysed to the corresponding phthalamic acid via rate-determining attack at the phthalimide carbonyl group.