Aryl Side Chains Research Articles

Manipulating electron linking units and side chains for high-performance all-polymer photodetectors with stability over 5000 h

All-polymer photovoltaic devices have attracted extensive attention for their promising applications in various flexible devices. Although abundant polymer donors with superior properties are developed, new polymer acceptors are urgently required to optimize or update the performances of the devices. Herein, three novel polymer acceptors, namely PY-DTT, PY-DTP-C, and PY-DTP-Ph, based on dithienothiophene (DTT) and dithienopyrrole (DTP) with alkyl and aryl side chains as the linking units respectively are synthesized and employed in the all-polymer photodetectors (all-PPDs). The PY-DTP-Ph shows broader absorption, stronger intermolecular interaction, and more coplanar molecular conformation compared with the other two acceptors. Blending with donor PM6, the PY-DTP-Ph based all-PPDs exhibit maximum responsivity of 292.1 mA W−1 and specific detectivity of 5.4 × 1013 cm Hz1/2 W−1 at a bias of −0.1 V. Furthermore, the device achieves fast response speed (τr/τf = 1.2/21.8 μs) and a large linear dynamic range of 105.0 dB. Intriguingly, the photodetectors present extraordinary air stability for 5000 h, attributing to the ideal miscibility and morphology of the blend films. These results demonstrate close relationships between the electron linking units, side chains and the basic properties of polymer acceptors, which in turn affects the performances of the photodetector devices.

Design, Synthesis, in Silico and in Vitro Evaluation of New Combretastatin A-4 Analogs as Antimitotic Antitumor Agents.

Combretastatin A-4 (CA-4) binds β-tubulin at the colchicine-binding site preventing tubulin from polymerizing into microtubules. CA-4 and cis combretastatin analogs isomerize to the trans form resulting in decreased cytotoxicity and anti-tubulin activity. However, the excellent anti-cancer potential and relatively simple molecular structure of CA-4, provide an encouraging starting point for the development of new, more stable and more potent anti-tubulin compounds. To synthesize a new series of 4-(3,4,5-trimethoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives (compounds 10-12) as analogs of CA-4, with different alkyl, and aryl side chain substituents at the triazole moiety (B-ring), resulting in permanent cis form. The newly synthesized CA-4 analogs were characterized by FT-IR, 1HNMR, 13CNMR, and HR-MS(ESI) techniques. Molecular docking studies including docking score (G) ADMET, DFT, and mlocular similarities were performed. The anti-proliferative activity of the new compounds against three human cancer cell lines was evaluated using the MTT assay, and their ability to inhibit tubulin polymerization, and consequently their effects on cell cycle progression and induction of apoptois were assessed. Molecular docking studies showed that compounds 11b and 11d exhibited the highest docking scores (-13.30 and -14.01 Kcal/mol, respectively) into colchicine-binding site, scores very close to the reference drug colchicine (-13.50 Kcal/mol), and that hydrogen bonding and hydrophobic interaction are essential for binding. The most active cytotoxic compound 11b had potent IC50 values ranging from 3.83 to 10.67 µM against the three human cancer cell lines, while exhibiting low cytotoxicity against non-cancer human WI-38, suggesting that compound 11b targets rapidly growing cancer cells. Moreover, compound 11b exhibited potent anti-tubulin activity which was comparable to CA-4. Targeting microtubules caused cell cycle arrest at the G2/M phase resulting in induction of apoptosis. These findings indicate that compound 11b is a promising β-tubulin-binding compound with antimitotic action that has the potential to treat cancer.

Inhibition of furin-like enzymatic activities and SARS-CoV-2 infection by osthole and phenolic compounds with aryl side chains

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread as a pandemic and caused damage to people’s lives and countries’ economies. The spike (S) protein of SARS-CoV-2 contains a cleavage motif, Arg-X-X-Arg, for furin and furin-like enzymes at the boundary of the S1/S2 subunits. Given that cleavage plays a crucial role in S protein activation and viral entry, the cleavage motif was selected as the target. Our previous fluorogenic substrate study showed that osthole, a coumarin compound, inhibits furin-like enzyme activity. In this study, we examined the potential activities of 15 compounds with a structure-activity relationship with osthole, and evaluated their protective ability against SARS-CoV-2 infection. Of the 15 compounds tested, compounds C1 and C2 exhibited the inhibitory effects of osthole against furin-like enzymatic activity; however, little or no inhibitory effects against furin activity were observed. We further examined the inhibition of SARS-CoV-2 activity by compounds C1 and C2 using a Vero E6 cell line that expresses the transmembrane protease serine 2 (TMPRSS2). Compounds C1, C2, and osthole effectively inhibited SARS-CoV-2 infection. Therefore, osthole and its derivatives can potentially be used as therapeutic agents against SARS-CoV-2.

Side-chain modification of non-fullerene acceptors for organic solar cells with efficiency over 18%

A new synthetic route to realize efficient screening of aryl side chains on the Y6 skeleton was reported, and then three acceptors with different side chains were synthesized. Among them, the BTP-OC6-based device exhibits the best PCE and stability.

Synthesis, In vitro Antibacterial and Antimycobacterial Activity and Docking Study of Thieno(3,2-e)(1,2,4)triazolo(1,5-c)pyrimidines

Background: Emergence of drug resistance and severe side effects with current an-titubercular drugs urges the development of more efficacious and safer new agents. The present study focused on this direction to develop new hetero-fused pyrimidines as potential antitubercu-lar agents. Objective: The objective of the study was to synthesize and assess the antibacterial and antimy-cobacterial activity of novel 1,2,4-triazole ring bearing hetero-fused thienopyrimidines (6a-j & 7a-j). Also to evaluate the binding pattern of synthesized molecules at the target site and study their ADME properties by in silico tools. Methods: Two series of hetero fused thienopyrimidines (6a-j & 7a-j) were synthesized and tested for their antibacterial potentiality against B. subtilis, S. aureus, E. coli, and K. pneumonia. Com-pounds with potential antibacterial activity were further tested for their antitubercular activity against Mycobacterium tuberculosis (MTB) H37Rv and an isoniazid (INH)-resistant clinical sam-ple of MTB using broth microdilution method. The binding efficacy at the enzyme site was eval-uated by the molecular docking study using pantothenate synthetase (MTB-PS) (PDB: 3IVX) as the target protein. Further, in silico ADME properties of title compounds were explored by Swiss ADME online tools. Results: In this study, few compounds were found promising in exhibiting potent inhibitory ac-tivity against E. coli and MTB. Among these compounds, 6h (MTB: MIC-17.13±0.88 μM) and 6i (MTB: MIC-17.55±0.72 μM) displayed significant antimycobacterial activity. The molecular docking results suggested the efficient binding of biologically potential molecules. Conclusion: Compounds bearing N-benzyl moiety at the core nucleus with a p-nitro aryl side chain (6h) exhibited significant antitubercular activity. In silico studies showed effective binding at the target site and also indicated good compatibility in ADME properties.

Intracellular delivery of messenger RNA to macrophages with surfactant-derived lipid nanoparticles

The broad biomedical applications of messenger RNA (mRNA)-based therapeutics rely heavily on the rapid development of mRNA delivery systems. In this study, dual-component lipid nanoparticles (LNPs) were developed for intracellular delivery of mRNA to macrophages. By screening a panel of quaternary ammonium compounds with varying alkyl or aryl side chains, a cationic surfactant containing two hexadecyl tails was found to be effective for mRNA delivery with the assistance of fusogenic lipids. Further investigating structure alterations and optimization of formulation parameters, we found that a surfactant-derived ionizable lipid mixed with a fusogenic lipid was capable of condensing mRNA and self-assembling into LNPs. Without using the PEGylated lipid, the resulting LNPs were able to render the exogenous mRNA resistant to hydrolysis by nucleases and displayed excellent biocompatibility, along with the capacity to deliver mRNA to hard-to-transfect. Overall, the dual-component nanocarrier provides a novel mRNA delivery platform for genetic engineering of macrophages.

Alkenylation and Arylation of Peptides via Ni-Catalyzed Reductive Coupling of α-C-Tosyl Peptides with Csp2 Triflates/Halides.

A Ni-catalyzed reductive cross-coupling between α-C-tosyl peptides and Csp2 triflates/halides has been developed. This protocol enables the formation of various unnatural di- and tripeptides containing vinyl and aryl side chains, and it expands the applications of Ni-catalyzed reductive cross-coupling in late-stage diversification of peptides.

Valorization of lignin components into gallate by integrated biological hydroxylation, O-demethylation, and aryl side-chain oxidation.

Converting lignin components into a single product is a promising way to upgrade lignin. Here, an efficient biocatalyst was developed to selectively produce gallate from lignin components by integrating three main reactions: hydroxylation, O-demethylation, and aryl side-chain oxidation. A rationally designed hydroxylase system was first introduced into a gallate biodegradation pathway–blocked Rhodococcus opacus mutant so that gallate accumulated from protocatechuate and compounds in its upper pathways. Native and heterologous O-demethylation systems were then used, leading to multiple lignin-derived methoxy aromatics being converted to gallate. Furthermore, an aryl side-chain oxidase was engaged to broaden the substrate spectrum. Consequently, the developed biocatalyst showed that gallate yields as high as 0.407 and 0.630 g of gallate per gram of lignin when alkaline-pretreated lignin and base-depolymerized ammonia fiber explosion lignin were applied as substrates, respectively. These results suggested that this rationally developed biocatalyst enabled the lignin valorization process to be simple and efficient.

Effect of chain length and branching on the in vitro metabolism of a series of parabens in human liver S9, human skin S9, and human plasma

Parabens are antimicrobial compounds used as preservatives in cosmetics, foods, and pharmaceuticals. Paraben exposure occurs through a variety of routes including dermal absorption, ingestion, and inhalation. Ester bond hydrolysis has been shown to be the predominant biotransformation for this chemical class. Here we evaluated a series of parabens of increasing alkyl chain length and branching in addition to the aryl side chain of phenyl paraben (PhP). We evaluated the parabens under full Michaelis-Menten (MM) parameters to obtain intrinsic clearance values and found different trends between human liver and skin, which correlate with the predominant esterase enzymes in those matrices, respectively. In liver, where carboxylesterase 1 (CES1) is the predominant esterase enzyme, the shorter chain parabens were more readily metabolized, while in skin, where carboxylesterase 2 (CES2) is the predominant esterase enzyme, the longer chain parabens were more readily metabolized. Alkyl chain branching reduced the hydrolysis rates relative to those for the straight chain compounds, while the addition of a phenyl group, as in PhP, showed an increase in hydrolysis, producing the highest observed hydrolysis rate for skin. These data summarize the structure-metabolism relationship for a series of parabens and contribute to the safety assessment of this class of compounds.

Synthesis, antibacterial action, and ribosome inhibition of deoxyspectinomycins

Spectinomycin, an aminocyclitol antibiotic, is subject to inactivation by aminoglycoside modifying enzymes (AMEs) through adenylylation or phosphorylation of the 6-hydroxy group position. In this study, the effects of deoxygenation of the 2- and 6-hydroxy group positions on the spectinomycin actinamine ring are probed to evaluate their relationship to ribosomal binding and the antimicrobial activities of spectinomycin, semisynthetic aminomethyl spectinomycins (amSPCs), and spectinamides. To generate these analogs, an improved synthesis of 6-deoxyspectinomycin was developed using the Barton deoxygenation reaction. 6-Dehydrospectinamide was also synthesized from spectinamide 4 to evaluate the H-bond acceptor character on the C-6 position. All the synthesized analogs were tested for antibacterial activity against a panel of Gram (+) and Gram (−) pathogens, plus Mycobacterium tuberculosis. The molecular contribution of the 2- and 6-hydroxy group and the aryl functionalities of all analogs were examined by measuring inhibition of ribosomal translation and molecular dynamics experiments with MM/GBSA analysis. The results of this work indicate that the 6-hydroxy group, which is the primary target of AMEs, is a required motif for antimicrobial activity in current analogs. Removal of the 6-hydroxy group could be partially rescued by offsetting ribosomal binding contributions made by the aryl side chains found in the spectinamide and amSPCs. This study builds on the knowledge of the structure–activity relationships of spectinomycin analogs and is being used to aid the design of next-generation spectinomycins.

Radical-mediated C-C cleavage of unstrained cycloketones and DFT study for unusual regioselectivity

The C-C σ-bond activation of unstrained cycloketones represents an ingenious and advanced technique in synthetic chemistry, but it remains a challenging area which has been largely underexplored. Herein we report an efficient strategy for the direct C-C cleavage of cyclohexanones and cyclopentanones. The cyclic C-C σ-bond is readily cleaved under mild conditions with the aid of an in situ formed side-chain aryl radical. Density functional theory calculations are carried out to shed light on the unusual regioselectivity of C-C bond cleavage. The reaction affords a variety of structurally diverse 3-coumaranones and indanones that widely exist in natural products and bioactive molecules, illustrating the synthetic value of this method.

Could Dissecting the Molecular Framework of β-Lactam Integrin Ligands Enhance Selectivity?

By dissecting the structure of β-lactam-based ligands, a new series of compounds was designed, synthesized, and evaluated toward integrins αvβ3, α5β1, and α4β1. New selective ligands with antagonist or agonist activities of cell adhesion in the nanomolar range were obtained. The best agonist molecules induced significant adhesion of SK-MEL-24 cells and Saos-2 cells as a valuable model for osteoblast adhesion. These data could lead to the development of new agents to improve cellular osseointegration and bone regeneration. Molecular modeling studies on prototypic compounds and αvβ3 or α5β1 integrin supported the notion that ligand carboxylate fixing to the metal ion-dependent adhesion site in the β-subunit can be sufficient for binding the receptors, while the aryl side chains play a role in determining the selectivity as well as agonism versus antagonism.

Discovery of amide-bridged pyrrolo[2,3-d]pyrimidines as tumor targeted classical antifolates with selective uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis

We previously showed that classical 6-substituted pyrrolo[2,3-d]pyrimidine antifolates bind to folate receptor (FR) α and the target purine biosynthetic enzyme glycinamide ribonucleotide formyltransferase (GARFTase) with different cis and trans conformations. In this study, we designed novel analogs of this series with an amide moiety in the bridge region that can adopt both the cis and trans lowest energy conformations. This provides entropic benefit, by restricting the number of side-chain conformations of the unbound ligand to those most likely to promote binding to FRα and the target enzyme required for antitumor activity. NMR of the most active compound 7 showed both cis and trans amide bridge conformations in ~1:1 ratio. The bridge amide group in the best docked poses of 7 in the crystal structures of FRα and GARFTase adopted both cis and trans conformations, with the lowest energy conformations predicted by Maestro and evidenced by NMR within 1 kcal/mol. Compound 7 showed ~3-fold increased inhibition of FRα-expressing cells over its non-restricted parent analog 1 and was selectively internalized by FRα over the reduced folate carrier (RFC), resulting in significant in vitro antitumor activity toward FRα-expressing KB human tumor cells. Antitumor activity of 7 was abolished by treating cells with adenosine but was incompletely protected by 5-aminoimidazole-4-carboxamide (AICA) at higher drug concentrations, suggesting GARFTase and AICA ribonucleotide formyltransferase (AICARFTase) in de novo purine biosynthesis as the likely intracellular targets. GARFTase inhibition by compound 7 was confirmed by an in situ cell-based activity assay. Our results identify a “first-in-class” classical antifolate with a novel amide linkage between the scaffold and the side chain aryl L-glutamate that affords exclusive selectivity for transport via FRα over RFC and antitumor activity resulting from inhibition of GARFTase and likely AICARFTase. Compound 7 offers significant advantages over clinically used inhibitors of this class that are transported by the ubiquitous RFC, resulting in dose-limiting toxicities.

An Organic Zeolite With 10 Å Diameter Pores Assembles From a Soluble and Flexible Building Block by Non-Covalent Interactions.

Two similar molecular building blocks, which both contain a hydrogen‐bonded nitro group, have been prepared and crystallised. One structure has more flexibility with a butyl side chain which allows an open framework organic zeolite to form with large 10 Å diameter pores, whereas the other structure has less flexibility with an aryl side chain and is close packed. The pore size is comparable with those of the aluminophosphate VPI‐5 (12 Å). It is concluded that some flexibility in the design of the building block for porous organic molecular materials was beneficial.

Role of Trifluoromethyl Substitution in Design of Antimalarial Quinolones: a Comprehensive Review.

Malaria represents a significant health issue, and novel effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. The most popular antimalarial drugs are focused on the 7-chloro-4-aminoquinoline [e.g., chloroquine (CQ), amodiaquine (AQ), isoquine (IQ), and tebuquine (TBQ)], artemisinin, and atovaquone systems. Recently, endochin has been used as a platform to design a variety of novel potent and safe antimalarial agents named endochin-like quinolones (ELQs). Also, antimalarial quinolones have been constructed from other quinolones drugs such as ICI-56780 and floxacrine. Trifluoromethyl substitution has provided a significant increase in the antimalarial response of many of the designed ELQs against Plasmodium-resistant strains and for invivo models. In particular, attachment of a substituted trifluoromethoxy (or trifluoromethyl in some cases) biaryl side chain at 2-, 3-, 4-, or 6-position of the quinolone core has shown to be crucially important to generate selective and potent novel ELQs. Furthermore, 6-chloro and 7-methoxy moieties on the quinolone core have been identified as essential pharmacophores when the trifluoromethoxy biaryl side chain is placed at 2- or 3-position of the quinolone core. Methyl or ethyl ester attached at 3-position is essential when the trifluoromethoxy aryl side chain is attached at 6- or 7-position of the quinolone core. Some promising ELQs are currently under clinical trials, representing an excellent platform for the design of new potent, selective, effective, and safe antimalarial drugs against emergent resistance malarial models.

A Simple Phenyl Group Introduced at the Tail of Alkyl Side Chains of Small Molecular Acceptors: New Strategy to Balance the Crystallinity of Acceptors and Miscibility of Bulk Heterojunction Enabling Highly Efficient Organic Solar Cells.

Research on fused-ring small-molecular-acceptors (SMAs) has deeply advanced the development of organic solar cells (OSCs). Compared to fruitful studies of ladder-type cores and end-caps of SMAs, the exploration of side chains is monotonous. The widely utilized alkyl and aryl side chains usually produce a conflicting association between SMAs' crystallinity and miscibility. Herein, a fresh idea about the modification of side chains is reported to explore the subtle balance between the crystallinity and miscibility. Specifically, a phenyl is introduced to the tail of the alkyl side chain whereby a new acceptor IDIC-C4Ph is reported. Moderately weakened crystallinity is observed, while maintaining preferred absorption profiles and face-on orientations. Concurrently, remarkably improved heterojunction morphologies and stacking orientations are detected. PBDB-T:IDIC-C4Ph devices exhibit greater efficiency of 11.50% than devices from alky and aryl modified acceptors. Notably, the as-cast OSCs of PBDB-TF:IDIC-C4Ph reveal outstanding FF over 76% with the best efficiency up to 13.23%. The annealed devices reveal further increased efficiency exceeding 14% with the state of the art FF of 78.32%. Overall, an effective but easily navigable approach is demonstrated to modulate the crystallinity of SMAs toward synergistically improved morphologies and molecular orientations of bulk heterojunction enabling highly efficient OSCs.

Abstract 2798: Folate receptor-targeted cancer chemotherapy with novel 6-substituted thieno[2,3-d]pyrimidine compounds with nitrogen and fluorine containing aromatic side chains as de novo purine biosynthesis inhibitors

Abstract Targeted cancer chemotherapy inhibits the growth of cancer cells by interfering with critical pathways required for tumor progression. Three major transporters are involved in membrane transport of folates into mammalian cells and include the reduced folate carrier (RFC), folate receptors (FRs) α and β, and proton-coupled folate transporter (PCFT). The clinically used agents methotrexate, pemetrexed, raltitrexed and pralatrexate are all transported by the ubiquitously expressed RFC into both tumor cells and normal tissues, and hence are non-selective. The lack of tumor selectivity results in dose-limiting toxicity. We reported 6-substituted thieno[2,3-d]pyrimidine (6TP) compounds with a phenyl side-chain and bridge lengths of 2-8 carbons as potent inhibitors that are selectively transported by FRs over RFC and inhibit proliferation of FR-expressing KB tumor cells with low nanomolar IC50s. The most potent compound (AGF50), a thieno[2,3-d]pyrimidine with a 4-carbon bridge and a phenyl side chain, showed FR selectivity over RFC and potent inhibition of de novo purine biosynthesis at least in part due to inhibition of glycinamide ribonucleotide formyltransferase (GARFTase). In this report, fluorine was strategically placed on the aryl side chain which could induce conformational restriction due to possible intramolecular fluorine-hydrogen bonding interactions. We found that fluorine substitution on the phenyl side-chain, ortho (o-) to L-glutamate (AGF304) improved potency and selectivity for FRα (4.5-fold) and FRβ (20-fold) compared to AGF50, as reflected in inhibition of proliferation of Chinese hamster ovary cells expressing human FRs. The pyridine nitrogen can also form H-bonds with NH of the L- glutamate amide, which could improve the potency and selectivity of 6TPs with pyridine side-chains. Analogs with systematic pyridine side-chain modifications, as well as ortho fluorine substitution on the pyridine ring, were designed, modeled, and synthesized. The 2',5'-pyridine analog AGF132 was ~9-fold more active toward FRα-expressing cells but approximately equipotent toward FRβ. The fluorinated 2',5'-pyridine analog AGF305 was ~5-fold less potent for FRα and was >50-fold more potent for FRβ compared to AGF132. AGF132, AGF304 and AGF305 inhibited growth of KB human tumor cells approximately equivalent to AGF50. Whereas adenosine completely protected cells from growth inhibition by the 6TPs, protection with 5-aminoimidazole-4-carboxamide (AICA) was incomplete, suggesting inhibition at AICA ribonucleotide formyltransferase (AICARFTase), along with GARFTase. Our 6TPs with aryl side-chain modifications are slated for further preclinical studies to identify potential clinical candidates that target the de novo purine biosynthesis pathway. Citation Format: Nian Tong, Aleem Gangjee, Adrianne W. Povrik, Carrie O. Connor, Jianjun Hou, Larry Matherly. Folate receptor-targeted cancer chemotherapy with novel 6-substituted thieno[2,3-d]pyrimidine compounds with nitrogen and fluorine containing aromatic side chains as de novo purine biosynthesis inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2798.

Azido Platform Surfaces for Post‐Functionalization with Aromatic Groups Using the Huisgen Reaction to Obtain High Water Adhesion

In this work, platform post‐modifications using the Huisgen reaction are reported. Various platform surfaces are developed and post‐functionalized with aryl side chains. The development of different conducting polymer platforms allows the study of the impact of the starting surface on the modified surface properties. Also in this work, different aryl side chains are investigated (with one, two, three, or four aromatic rings) in order to investigate the impact of the side chain on the final surface feature. All the combinations (surface vs aryl side chain) are investigated for their wettability. Highly hydrophobic features are observed with apparent contact angles θ higher than 140° and extremely high water adhesion. Surface morphologies are also investigated and important changes in morphology are observed after surface post‐functionalization. The reported strategy to develop various highly hydrophobic surfaces with high water adhesion feature can be a powerful strategy for water trap elaboration. image

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold.

Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure-activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.

Boronic Acid Transition State Inhibitors Active against KPC and Other Class A β-Lactamases: Structure-Activity Relationships as a Guide to Inhibitor Design.

Boronic acid transition state inhibitors (BATSIs) are competitive, reversible β-lactamase inhibitors (BLIs). In this study, a series of BATSIs with selectively modified regions (R1, R2, and amide group) were strategically designed and tested against representative class A β-lactamases of Klebsiella pneumoniae, KPC-2 and SHV-1. Firstly, the R1 group of compounds 1a to 1c and 2a to 2e mimicked the side chain of cephalothin, whereas for compounds 3a to 3c, 4a, and 4b, the thiophene ring was replaced by a phenyl, typical of benzylpenicillin. Secondly, variations in the R2 groups which included substituted aryl side chains (compounds 1a, 1b, 1c, 3a, 3b, and 3c) and triazole groups (compounds 2a to 2e) were chosen to mimic the thiazolidine and dihydrothiazine ring of penicillins and cephalosporins, respectively. Thirdly, the amide backbone of the BATSI, which corresponds to the amide at C-6 or C-7 of β-lactams, was also changed to the following bioisosteric groups: urea (compound 3b), thiourea (compound 3c), and sulfonamide (compounds 4a and 4b). Among the compounds that inhibited KPC-2 and SHV-1 β-lactamases, nine possessed 50% inhibitory concentrations (IC50s) of ≤ 600 nM. The most active compounds contained the thiopheneacetyl group at R1 and for the chiral BATSIs, a carboxy- or hydroxy-substituted aryl group at R2. The most active sulfonamido derivative, compound 4b, lacked an R2 group. Compound 2b (S02030) was the most active, with acylation rates (k2/K) of 1.2 ± 0.2 × 10(4) M(-1) s(-1) for KPC-2 and 4.7 ± 0.6 × 10(3) M(-1) s(-1) for SHV-1, and demonstrated antimicrobial activity against Escherichia coli DH10B carrying blaSHV variants and blaKPC-2 or blaKPC-3 and against clinical strains of Klebsiella pneumoniae and E. coli producing different class A β-lactamase genes. At most, MICs decreased from 16 to 0.5 mg/liter.