Lactam Ring Research Articles

Degradation of Penicillinic Antibiotics and β-Lactamase Enzymatic Catalysis in a Biomimetic Zn-Based Metal-Organic Framework.

β-Lactam antibiotics are one of the most commonly prescribed drugs to treat bacterial infections. However, their use has been somehow limited given the emergence of bacteria with resistance mechanisms, such as β-lactamases, which inactivate them by degrading their four-membered β-lactam rings. So, a total knowledge of the mechanisms governing the catalytic activity of β-lactamases is required. Here, we report a novel Zn-based metal-organic framework (MOF, 1), possessing functional channels capable to accommodate and interact with antibiotics, which catalyze the selective hydrolysis of the penicillinic antibiotics amoxicillin and ceftriaxone. In particular, MOF 1 degrades, very efficiently, the four-membered β-lactam ring of amoxicillin, acting as a β-lactamase mimic, and expands the very limited number of MOFs capable to mimic catalytic enzymatic processes. Combined single-crystal X-ray diffraction (SCXRD) studies and density functional (DFT) calculations offer unique snapshots on the host-guest interactions established between amoxicillin and the functional channels of 1. This allows to propose a degradation mechanism based on the activation of a water molecule, promoted by a Zn-bridging hydroxyl group, concertedly to the nucleophilic attack to the carbonyl moiety and the cleaving of C-N bond of the lactam ring.

Pd‐Catalyzed Intramolecular Hydroaminocarbonylation of 3‐Allyl‐4‐arylaminocoumarins: Synthesis of Six‐ and Seven‐membered Ring Lactams Fused to the Coumarin Scaffold

AbstractA protocol has been developed for the synthesis of six‐ and seven‐membered ring lactams fused to coumarins through a hydroaminocarbonylation reaction catalyzed by palladium. The catalytic system (PdBr2/Xantphos) provided a strategy for the synthesis of seven‐membered ring lactams with good isolated yield and regioselectivity. Control of selectivity by the substrate in the synthesis of six‐membered ring lactams was observed. Control reactions showed the importance of the hydrogen in the cyclocarbonylation reaction, and NMR data supported the role of the hydride palladium species as a catalytic precursor. A preliminary screening of the cytotoxic activity of coumarin‐fused lactams against six cancer cell lines was evaluated. The biological tests indicated that both the size of the heterocycle and presence of a substituent on the aromatic ring affected the inhibition of cell growth.

The Activity of Some Antibiotics Depend on Stereochemistry of Them (Its Structure)

The chiral carbon in biological compounds lead to its activity, for example, the beta lactam ring contains two carbon centers carbon number three and carbon number four both are chiral carbon. This chirality plays important role in the activity and bind with structures activity relationship. Also the ofloxacin act on topoisomerase which required for protein Synthesis of microorganism, the ofloxacin when become Levo isomer not only racemic mixture the activity is more than the racemic or Dextro isomer. Also, the old Antibiotics Chloramphenicol the RR’ isomers only active not the other isomers of Chloramphenicol.

Experimental and kinetic modelling studies on the gas hydrate inhibition effect of PVP K-90 in drilling fluids

The hydrate inhibitors play a very important role in preventing hydrate growth inside the drilling fluid systems, which is desirable for smooth drilling operation. It has been demonstrated in several scenarios that the water-soluble polymer such as polyvinyl pyrrolidone (PVP K-90) efficiently reduces hydrate formation rates. In this study, the influence of on hydrate inhibition in predesigned drilling fluids in presence of a mixture gas of methane, ethane and propane has been investigated. As the concentration of the PVP K-90 increase, the induction time continues to increase. The rheological studies of drilling fluids conducted at different temperature and pressure condition with varying concentration of indicates their better performance. The chemical structure of polymer is a single 5-membered lactam ring attached to a carbon backbone which is responsible for the inhibition effect of the drilling fluid samples. The large concentration range tested allows unprecedented visualization of the shifting of formation rate in compare to pure water. Hydrate formation rate appears to reduce as concentration of increases from 0.1 wt% to 0.7 wt%. The results suggest that increasing the concentration of the inhibitor up to 0.7 wt% may reach to a level that saturates all the growth sites and there are enough PVP K-90 molecules available to block the hydrate crystal growth, which significantly reduces the formation rate. The experimental investigation offers new understanding of the operational mechanics of kinetic hydrate inhibitor (KHI) in drilling operations.

Skeletal Transformation of Oxindoles into Quinolinones Enabled by Synergistic Copper/Iminium Catalysis

We describe a synergistic Cu/secondary amine catalysis for skeletal transformation of an oxindole core into a quinolinone skeleton, which generates several structurally new pyridine-fused quinolinones. The synergistic reactions allow expansion of a five-membered lactam ring by radical cation-triggered C-C bond cleavage and enable a further intramolecular cyclization with the aim to construct totally distinct core skeletons.

Facile Synthesis of Isoindolinones via Radical-Mediated Intramolecular Coupling of Two C–H Bonds

AbstractA metal-free method for the construction of 3,3-dimethyl isoindolinones via radical-mediated intramolecular coupling of two C–H bonds of N,N-diisopropyl benzamides was developed. The reactions can proceed in moderate to high yield and with excellent chemoselectivity. A reaction sequence of the formation of an alkyl radical via oxidative cleavage of alkyl C–H bond and the formation of lactam ring via intramolecular homolytic aromatic substitution was proposed.

Design, synthesis and characterization of novel substituted pyrazol-azetidin-2-one derivatives for their antimicrobial activity

A novel method is elucidated herein, describing the synthesis of novel 3-chloro-4-(2-substituted phenyl)-1-( 4'-((1-(5-( 4-substituted phenyl)-3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) ethylidene) amino)-[1,1'-biphenyl]-4-yl) azetidin-2-one, consisting of a pyrazol motif (prepared from chalcone) and a lactam ring ( synthesized from Schiff base of aromatic aldehyde) as a potential antimicrobial agent. The structural elucidation of the synthesized compounds have been confirmed from the elemental analysis, UV-Vis absorption spectroscopy, IR, 1H NMR and mass spectral studies. The novel compounds have been subjected to in vitro antimicrobial screening against certain gram positive (S. aureus, B. subtilis) and gram negative (P. aeruginosa, E. coli) bacterial species. Compounds Vb, Vd and Ve are the most potent amongst all the synthesized compounds against the tested microbes.

A General Synthesis of Dihydronaphthyridinones with Aryl-Substituted Quaternary Benzylic Centers

A variety of 7,8-dihydro-1,6-naphthyridin-5(6H)-ones and 3,4-dihydro-2,7-naphthyridin-1(2H)-ones with quaternary centers and aryl substitutions at the benzylic carbon were synthesized with a new 3-step, 2-pot method. The first step is an SNAr using widely available 2- and 4-chloronicotinate esters and tertiary benzylic nitriles. The last two steps are a one-pot selective nitrile reduction in the presence of various heterocycles followed by a lactam ring closure of the free amine on the ester.

Treatment of amoxicillin-containing wastewater by Trichoderma strains selected from activated sludge

This study screened a Trichoderma strain (Trichoderma pubescens DAOM 166162) from activated sludge to solve the limitation of traditional biological processes in the treatment of amoxicillin (AMO) containing wastewater. The mechanism of the removal of AMO wastewater by T. pubescens DAOM 166162 (TPC) was studied. AMO resulted in a higher protein percentage in the extracellular polymeric substances (EPS) secreted by TPC, which facilitated the removal of AMO from the wastewater. Fourier transform infrared spectroscopy and excitation-emission matrix were used to characterize EPS produced by metabolizing different carbon sources. It was found that the hydroxyl group was the primary functional group in EPS. The life activity of TPC was the cause of the pH rise. The main pathway of degradation of AMO by TPC was the hydroxyl group uncoupling the lactam ring and the hydrolysis of AMO in an alkaline environment. The removal efficiency of AMO in wastewater by TPC was >98 % (24 h), of which the biodegradation efficiency was 70.01 ± 1.48 %, and the biosorption efficiency was 28.44 ± 2.97 %. In general, TPC is an effective strain for treating wastewater containing AMO. This research provides a new idea for AMO wastewater treatment.

Engineering piperlongumine-inspired analogs as Nrf2-dependent neuroprotectors against oxidative damage by an electrophilicity-based strategy.

Oxidative stress contributes significantly to the development of neurodegenerative diseases, thus developing nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent neuroprotectors is highly required for either prevention or treatment of these diseases. This work highlights an electrophilicity-based strategy that allows finding more active Nrf2-dependent neuroprotectors than natural piperlongumine (PL). Electrophilic modification was applied on both the exocylic and endocyclic Michael acceptors of PL, which includes placement of an electron-withdrawing trifluoromethyl group on its aromatic ring in the ortho, meta, or para position to the exocyclic olefin, and further introduction of an electron-withdrawing α-chlorine on its lactam ring. From a panel of PL analogs, we identified PLCl-4CF3, characterized by the presence of p-trifluoromethyl group and α-chlorine, to be significantly superior to the parent PL in protecting PC12cells from oxidative damage induced by 6-hydroxydopamine hydrochloride. Mechanistic studies reveal that the increased electrophilicity of PLCl-4CF3 in its two Michael acceptors allows its ability to covalently modify Cys-151 at Keap1, facilitating inhibition against Nrf2 ubiquitination, translocation of Nrf2 into the nucleus, induction of phase 2 enzymes and final protection of PC12cells from oxidative damage.

Reactions of 3-Hydroxy-2-phenyl-1H-benzo[e]isoindol-1-one: A Route to 3-Hydroxy-/3-anilinobenzo[e]indan-1-ones and Benzo[f]phthalazin-1(2H)-ones

New hydroxy- and anilinoindanone derivatives 3 and 4 were synthesized starting from 3-hydroxybenzo[e]isoindolinone 1 via the addition of alkyllithium (s-BuLi, n-BuLi, MeLi or i-PrLi) to the carbonyl group, followed by lactam ring opening and, finally, an intramolecular cyclization leading to target compounds. The same starting material was used for the preparation of the new benzo[f]phthalazinone derivatives 12-16 through multi-step reactions. The target derivative 16 was obtained from the corresponding bromolactam 15 by the Buchwald-Hartwig amination. Structures of the obtained compounds were confirmed by the NMR spectra.

Total Synthesis of the Proposed Structure of (-)-Novofumigatamide, Isomers Thereof, and Analogues. Part I.

The total synthesis of the suggested structure of (−)-novofumigatamide, a natural product containing a C3-reverse prenylated N-acetyl-exo-hexahydropyrrolo[2,3-b]indole motif fused to a 10-membered ring lactam, was achieved using the macrolactam formation in advance of a diastereoselective bromocyclization and reverse prenylation steps. Since the NMR data of the synthetic sample did not match those of the natural product, the endo-bromo precursor of a N-Boc analogue and additional diastereomers derived from l-Trp were also synthesized. Five alternative synthetic routes, which differed in the order of final key steps used for the construction of the 10-membered ring lactam and the hexahydropyrrolo[2,3-b]indole framework within the polycyclic skeleton and also in the amide bond selected for the ring-closing of the macrolactam, were thoroughly explored. Much to our dismay, the lack of spectroscopic correlations between the proposed structure of natural (−)-novofumigatamide and the synthetic products suggested a different connectivity between the atoms. Additional synthetic efforts to assemble alternative structures of the natural product and isomers thereof (see accompanying paper; DOI: 10.1021/acs.joc.2c01228) further highlighted the frustrating endeavors toward the identification of a natural product.

One-Pot Chemoenzymatic Synthesis of Microviridin Analogs Containing Functional Tags.

Microviridins are a prominent family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) featuring characteristic lactone and lactam rings. Their unusual cage-like architecture renders them highly potent serine protease inhibitors of which individual variants specifically inhibit different types of proteases of pharmacological interest. While posttranslational modifications are key for the stability and bioactivity of RiPPs, additional attractive properties can be introduced by functional tags. To date - although highly desirable - no method has been reported to incorporate functional tags in microviridin scaffolds or the overarching class of graspetides. In this study, a chemoenzymatic in vitro platform is used to introduce functional tags in various microviridin variants yielding biotinylated, dansylated or propargylated congeners. This straightforward approach paves the way for customized protease inhibitors with built-in functionalities that can help to unravel the still elusive ecological roles and targets of this remarkable class of compounds and to foster applications based on protease inhibition.

Regioselectivity in Wacker oxidations of internal alkenes: antiperiplanar effects?

Computational chemistry, with considerable effort, was used to elucidate the reason for regioselectivity (12:1 distal:proximal product distribution) in a published Wacker oxidation of internal alkenes with a homoallylic lactam ring. Such a distribution is reproduced by a non-chelating reaction pathway; chelated intermediates are found to be too high in energy. Despite much speculation of chelation effects in the literature, this particular result is most probably an antiperiplanar field effect with no chelation. Partial charge data are provided to support the proposed antiperiplanar effect. The great care needed in modelling Wacker oxidations is emphasized, but optimism is offered that its various product mysteries can be elucidated on a case-by-case basis.

Counterion-Mediated Enantioconvergent Synthesis of Axially Chiral Medium Rings.

There are few enantioconvergent reactions in which racemic substrates bearing multiple stereochemical features are converted into products with high levels of diastereo- and enantiocontrol. Here, we disclose a process for the highly enantio- and diastereoselective syntheses of medium ring lactams via an intramolecular counterion-directed C-alkylation reaction. The treatment of racemic biaryl anilides that exist as a complex mixture of enantiomers and diastereoisomeric conformers by virtue of multiple axes of restricted rotation with a quinidine-derived ammonium salt under basic conditions affords medium ring lactams bearing elements of both axial and point chirality via an enolate-driven configurational relaxation process. Thermal equilibration of the syn- and anti-product diasteroisomers has demonstrated that the barriers to bowl inversion are >124 kJ mol-1. We propose that the chiral ammonium salt differentiates between a complex and rapidly equilibrating mixture of enolate and rotational isomers, ultimately leading to highly enantioselective alkylative ring closure. This dynamic and enantioconvergent process offers an operationally simple approach to the synthesis of valuable chiral medium ring lactams for which there are few catalytic and enantioselective approaches.

Synthesizes, characterization, molecular docking and in vitro bioactivity study of new compounds containing triple beta lactam rings

Penicillin bioactivity is continuously decreased due to the misuses by people which resulted in an antibiotics resistance. However, B-lactam ring is still an effect group the attack bacterial infection. In this study, we aimed to synthesize compounds with triple B-lactam rings and study in vitro their bioactivity. Schiff bases were followed to form two effective ligands involving triple B-lactam rings that were also docked against Penicillin binding protein to show their abilities through computational simulation studies. The synthesis of the compounds was mainly performed in two major steps: the first step was to form three Schiff bases of the compound named as BTTP compound and the second step to perform a cyclisation to produce triple B-lactam rings named as BTTCDP compounds. The prepared compounds were then confirmed using various routinely spectroscopic methods such as FTIR, NMR and CHN techniques. In vitro study showed (MIC in µg ml−1) ranged from (0.254 and 0.568), respectively for both ligands. However, no inhibition was shown against fungus which could be considered as specific antibacterial. The molecular docking study showed the pockets of the binding with minimum free energy about -8.9 and -9.0 kcal/mol. All to gather, the two novel compounds containing triple B-lactam rings showed an effective bioactivity that are promising for in vivo studies in future.

RECENT TREND ON KNOWN PYRAZOLONE ENDOWED DERIVATIVES: ANOVERVIEW

Pyrazolone is a lactam ring with five-membered and 2-Nitrogen and 1-ketonic groups in its structure. Antimalarial, antifungal, antimycobacterial, antibacterial, anti-inflammatory, anticancer, gastric secretion stimulatory, antidepressant and antifilarial properties are also found in pyrazolones. They are also used in the extraction and separation of various metal ions, as well as precursors for dyes, pigments, insecticides and chelating agents. The excellent therapeutic qualities of pyrazolone-related medicines have prompted medicinal chemistry to develop a slew of new chemotherapeutic treatments. The synthesis of pyrazolone and numerous structural reactions may be done in a variety of ways, which opens up a lot of possibilities in the field of medicinal chemistry. This article mainly reports the chemistry, novel synthesis and biological activity of Pyrazolones and their derivatives.

Synthesis and Emergent Photophysical Properties of Diketopyrrolopyrrole-Based Supramolecular Self-Assembly.

Diketopyrrolopyrrole (DPP)-based molecular semiconductors exhibit intriguing optical and charge transport properties. Herein, we rationally design a series of electronically identical but structurally distinct Hamilton receptor (HR)-based supramolecular assembly of DPP. The HR endows supramolecular assemblies via hydrogen bonding with enhanced structural ordering and excitonic couplings. The mechanism of supramolecular self-assembly was probed by diffusion ordered spectroscopy (DOSY) nuclear magnetic resonance (NMR) and solid-state IR spectroscopy studies. We investigated the morphology of self-assembly, photophysical and electrochemical properties and compared them with the identical DPP molecular structures without HRs. The microstructure of self-assembly was probed with atomic force microscopy in thin films. Subsequently, the influence of solid-state packing was studied by single-crystal X-ray diffraction. The single-crystal structure of HR-TDPP-C20 reveals slipped stack arrangements between the two neighboring chromophores with π–π stacking distance and slip angle of 3.55 Å and 35.4°, respectively. Notably, the slight torsional angle of 1° between thiophene and lactam rings and small π–π stacking distance suggest a significant intermolecular coupling between thiophene (D) and lactam (A) rings. This intramolecular coupling between two π–π chromophore stacks manifests in their optical properties. In this manuscript, we report rational design and synthesis of supramolecular self-assembly of DPP with a collection of compelling structural and optical properties.

Design, Molecular Docking, Synthesis of Aromatic Amino Acids Linked to Cephalexin.

Infections caused by bacteria have a significant impact on public health. Chemical synthesis of new derivatives of cephalexin inked to amino acid (tryptophan or histidine) through an amide bond at the acyl side chain is achieved. This is a new
 approach of incorporating, tryptophan and histidine into the the primary amino group of cephalexin, in order to provide a bulky group very close to the β-lactam ring. This chemical addition act as isosteric group to the alkoximino that protect beta lactam ring from bacterial beta lactamase enzyme. The new derivatives may show resistance to β-lactamases, improve activity and pharmacokinetic properties and may give new life for old drugs that are susceptible to hydrolysis by most β-lactamases. The chemical structures of these derivatives were confirmed by: FTIR, 1H-NMR spectroscopy, elemental micro analysis and some physical properties. Molecular docking on serine beta lactamase and prediction of ADME parameters were recorded using GOLD suite and Swiss ADME software respectively. Docking scores of the new derivatives of Cephalexin on β-lactamases were higher than those of Cephalexin, which may indicate better activity

Remote Stereoelectronic Effects in Pyrrolidone- and Caprolactam-Substituted Phenols: Discrepancies in Antioxidant Properties Evaluated by Electrochemical Oxidation and H-Atom Transfer Reactivity.

New antioxidants are commonly evaluated via two main approaches, i.e., the ability to donate an electron and the ability to intercept free radicals. We compared these approaches by evaluating the properties of 11 compounds containing both antioxidant moieties (mono- and polyphenols) and auxiliary pharmacophores (pyrrolidone and caprolactam). Several common antioxidants, such as butylated hydroxytoluene (BHT), 2,3,5-trimethylphenol (TMP), quercetin, and dihydroquercetin, were added for comparison. The antioxidant properties of these compounds were determined by their rates of reaction with 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and their oxidation potentials from cyclic voltammetry. Although these methods test different chemical properties, their results correlate reasonably well. However, several exceptions exist where the two methods give opposite predictions! One of them is the different behavior of mono- and polyphenols: polyphenols can react with DPPH more than an order of magnitude faster than monophenols of a similar oxidation potential. The second exception stems from the size of a "bystander" lactam ring at the benzylic position. Although the phenols with a seven-membered lactam ring are harder to oxidize, the sterically nonhindered compounds react with DPPH about 2× faster than the analogous five-membered lactams. The limitations of computational methods, especially those based on a single parameter, are also evaluated and discussed.