Passerini reaction – Amine Deprotection – Acyl Migration (PADAM): a convenient strategy for the solid-phase preparation of peptidomimetic compounds

beta-Acylamino-alpha-hydroxyamides and beta-acylamino-alpha-oxoamides, compounds known to be potent protease inhibitors, can be conveniently prepared with a highly convergent strategy involving a Passerini multicomponent reaction between a N-protected alpha-aminoaldehyde, a carboxylic acid and an isocyanide. After N-deprotection and concomitant acyl migration the desired beta-acylamino-alpha-hydroxyamide moiety is obtained and can be further elaborated, for example via oxidation of the secondary alcohol group. In this paper we report the studies that have been carried out in order to transfer this synthetic methodology onto polystyrene resin, using a photocleavable linker and a N-Boc protecting strategy.     

The Higgs sector of the minimal <Emphasis Type="Italic">B</Emphasis>−<Emphasis Type="Italic">L</Emphasis> model at future Linear Colliders

We investigate the phenomenology of the Higgs sector of the minimal B−L extension of the Standard Model at a future e ⁺ e ⁻ Linear Collider. We consider the discovery potential of both a sub-TeV and a multi-TeV machine. We show that, within such a theoretical scenario, several novel production and decay channels involving the two physical Higgs states, precluded at the LHC, could experimentally be accessed at such machines. Amongst these, several Higgs signatures have very distinctive features with respect to those of other models with enlarged Higgs sector, as they involve interactions of Higgs bosons between themselves, with Z′ bosons as well as with heavy neutrinos. In particular, we present the scope of the Z′ strahlung process for single and double Higgs production, the only suitable mechanism enabling one to access an almost decoupled heavy scalar state (therefore outside the LHC range).     

A perturbed gamma degradation process with degradation dependent non‐Gaussian measurement errors

This paper proposes and illustrates a new perturbed gamma degradation process where the measurement error is modeled as a non‐Gaussian random variable that depends stochastically on the actual degradation level. The expression of the likelihood function for a generic set of noisy degradation measurements is derived, and the expression of the remaining useful life distribution of a degrading unit that fails when its degradation level exceeds a given threshold limit is formulated. A particle filter method is suggested, which allows one to compute the likelihood function and to estimate the remaining useful life distribution in a quick yet efficient manner. In addition, a closed‐form approximation of the perturbed gamma process is proposed to use in the special, yet meaningful, case where the standard deviation of the measurement error depends linearly on the actual degradation level. Finally, an applicative example is discussed, where the parameters of the perturbed gamma process, the remaining useful life distribution, and the mean remaining useful life of the degrading units are estimated from a set of noisy real degradation data.     

Introduction of permanently charged groups into PEGA resins leads to improved biotransformations on solid support

The application of biotransformations in solid phase synthesis is an attractive alternative to chemical methodologies. An important issue that needs to be addressed in this context is accessibility of functional groups within a porous polymer to the biocatalyst. This paper shows that such accessibility can be improved for penicillin G amidase by introducing permanent charges into the polymer. The effect appears to be due to better swelling of the polymer in buffer and to electrostatic interactions between polymer and enzyme.     

The catalytic mechanism of indole-3-glycerol phosphate synthase (IGPS) investigated by electrospray ionization (tandem) mass spectrometry

An enzymatic reaction has been monitored by on-line direct infusion electrospray ionization (tandem) mass spectrometry. Using this fast and sensitive technique, a key and transient intermediate of Mycobacterium tuberculosis indole-3-glycerol phosphate synthase (IGPS)-catalyzed reaction has been trapped. The reaction catalyzed by indole-3-glycerol phosphate synthase is part of the tryptophan biosynthetic pathway, and is not present in mammals, including humans. This peculiarity renders this enzyme a potential target for the development of biospecific agents with potential anti-TB activity. The present results indicate the presence of two intermediates in the mechanism of this enzymatic reaction.     

Ugi multicomponent reaction followed by an intramolecular nucleophilic substitution: convergent multicomponent synthesis of 1-sulfonyl 1,4-diazepan-5-ones and of their benzo-fused derivatives

A short, two-step approach to the synthesis of diazepane or diazocane systems, based on a Ugi multicomponent reaction followed by a subsequent intramolecular SN2 reaction was studied. 1-sulfonyl tetrahydrobenzo[e]-1,4-diazepin-1-ones 1 were obtained in very high yield through a Ugi multicomponent reaction followed by Mitsunobu cyclization. On the other hand, aliphatic 1-sulfonyl 1,4-diazepan-5-ones 2 could be obtained employing different cyclization conditions (sulfuryl diimidazole). A similar approach toward diazocane rings using hydroxamates as nucleophiles was less successful, affording only O-cyclized adducts or unexpected side products. A mechanistic explanation of the observed outcomes is proposed.     

Ultrasound-Assisted Synthesis of 4-Alkoxy-2-methylquinolines: An Efficient Method toward Antitubercular Drug Candidates

Tuberculosis (TB) has been described as a global health crisis since the second half of the 1990s. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB in humans, is a very successful pathogen, being the main cause of death in the population among infectious agents. In 2019, it was estimated that around 10 million individuals were contaminated by this bacillus and about 1.2 million succumbed to the disease. In recent years, our research group has reported the design and synthesis of quinoline derivatives as drug candidates for the treatment of TB. These compounds have demonstrated potent and selective growth inhibition of drug-susceptible and drug-resistant Mtb strains. Herein, a new synthetic approach was established providing efficient and rapid access (15 min) to a series of 4-alkoxy-6-methoxy-2-methylquinolines using ultrasound energy. The new synthetic protocol provides a simple procedure utilizing an open vessel system that affords the target products at satisfactory yields (45–84%) and elevated purities (≥95%). The methodology allows the evaluation of a larger number of molecules in assays against the bacillus, facilitating the determination of the structure–activity relationship with a reduced environmental cost.     

Conformational analysis of cis-2-halocyclohexanols; solvent effects by NMR and theoretical calculations

Conformational problems often involve very small energy differences, even low as 0.5 kcal mol(-1). This accuracy can be achieved by theoretical methods in the gas phase with the appropriate accounting of electron correlation. The solution behavior, on the other hand, comprises a much greater challenge. In this study, we conduct and analysis for cis-2-fluoro-, cis-2-chloro-, and cis-2-bromocyclohexanol using low temperature NMR experiments and theoretical calculations (DFT, perturbation theory, and classical molecular dynamics simulations). In the experimental part, the conformers' populations were measured at 193 K in CD(2)Cl(2), acetone-d(6), and methanol-d(4) solutions; the preferred conformer has the hydroxyl group in the equatorial and the halogen in the axial position (ea), and its population stays at about 60-70%, no matter the solvent or the halogen. Theoretical calculations, on the other hand, put the ae conformer at a lower energy in the gas phase (MP2/6-311++G(3df,2p)). Moreover, the theoretical calculations predict a markedly increase in the conformational energy on going from fluorine to bromine, which is not observed experimentally. The solvation models IEF-PCM and C-PCM were tested with two different approaches for defining the atomic radii used to build the molecular cavity, from which it was found that only with explicit consideration of hydrogens can the conformational preference be properly described. Molecular dynamic simulations in combination with ab initio calculations showed that the ea conformer is slightly favored by hydrogen bonding.