Synthesis Of Analogues Research Articles

N α -acetyl-L-ornithine deacetylase from Escherichia coli and a ninhydrin-based assay to enable inhibitor identification.

Bacteria are becoming increasingly resistant to antibiotics, therefore there is an urgent need for new classes of antibiotics to fight antibiotic resistance. Mammals do not express N ɑ -acetyl-L-ornithine deacetylase (ArgE), an enzyme that is critical for bacterial survival and growth, thus ArgE represents a promising new antibiotic drug target, as inhibitors would not suffer from mechanism-based toxicity. A new ninhydrin-based assay was designed and validated that included the synthesis of the substrate analog N 5, N 5-di-methyl N α-acetyl-L-ornithine (kcat/Km = 7.32 ± 0.94 × 104M-1s-1). This new assay enabled the screening of potential inhibitors that absorb in the UV region, and thus is superior to the established 214nm assay. Using this new ninhydrin-based assay, captopril was confirmed as an ArgE inhibitor (IC50 = 58.7μM; Ki = 37.1 ± 0.85μM), and a number of phenylboronic acid derivatives were identified as inhibitors, including 4-(diethylamino)phenylboronic acid (IC50 = 50.1μM). Selected inhibitors were also tested in a thermal shift assay with ArgE using SYPRO Orange dye against Escherichia coli ArgE to observe the stability of the enzyme in the presence of inhibitors (captopril Ki = 35.9 ± 5.1μM). The active site structure of di-Zn EcArgE was confirmed using X-ray absorption spectroscopy, and we reported two X-ray crystal structures of E. coli ArgE. In summary, we describe the development of a new ninhydrin-based assay for ArgE, the identification of captopril and phenylboronic acids as ArgE inhibitors, thermal shift studies with ArgE + captopril, and the first two published crystal structures of ArgE (mono-Zn and di-Zn).

Direct testing of natural twister ribozymes from over a thousand organisms reveals a broad tolerance for structural imperfections.

ABSTRACTTwister ribozymes are an extensively studied class of nucleolytic RNAs. Thousands of natural twisters have been proposed using sequence homology and structural descriptors. Yet, most of these candidates have not been validated experimentally. To address this gap, we developed CHiTA (Cleavage High-Throughput Assay), a high-throughput pipeline utilizing massively parallel oligonucleotide synthesis and next-generation sequencing to test putative ribozymesen massein a scarless fashion. As proof of principle, we applied CHiTA to a small set of known active and mutant ribozymes. We then used CHiTA to test two large sets of naturally occurring twister ribozymes: over 1, 600 previously reported putative twisters and ∼1, 000 new candidate twisters. The new candidates were identified computationally in ∼1, 000 organisms, representing a massive increase in the number of ribozyme-harboring organisms. Approximately 94% of the twisters we tested were active and cleaved site-specifically. Analysis of their structural features revealed that many substitutions and helical imperfections can be tolerated. We repeated our computational search with structural descriptors updated from this analysis, whereupon we identified and confirmed the first intrinsically active twister ribozyme in mammals. CHiTA broadly expands the number of active twister ribozymes found in nature and provides a powerful method for functional analyses of other RNAs.GRAPHICAL ABSTRACT

Unexpectedly Regioselective Diels-Alder Reactions of New Unsymmetrical Benzoquinones: A Convenient Synthetic Entry to Uniquely Substituted Decalins.

We report flexible synthesis of new unsymmetrically 2,6-disubstituted benzoquinones (33 examples) and a systematic study of their reactivity in the Diels-Alder reaction. The Diels-Alder reactions of selected unsymmetrical benzoquinones with seemingly similar substituents were found to proceed with high regioselectivity and the formation of selected experimentally observed main products was rationalized by theoretical (DFT) calculations. The findings can be exploited in the convenient preparation of densely substituted and stereochemically defined decalins with unique angular substituents at ring fusion. We also demonstrate the usefulness of this methodology in complex molecule synthesis through the total synthesis of a novel forskolin analog possessing an ethyl group at the fusion of the rings B and C.

Novel Brassinosteroid Analogues with 3,6 Dioxo Function, 24-Nor-22(S)-Hydroxy Side Chain and p-Substituted Benzoate Function at C-23-Synthesis and Evaluation of Plant Growth Effects.

Brassinosteroids (BRs) are an important group of polyhydroxylated naturally occurring steroidal phytohormones found in the plant kingdom in extremely low amounts. Due to the low concentrations in which these compounds are found, much effort has been dedicated to synthesizing these compounds or their structural analogs using natural and abundant sterols. In this work, we report the synthesis of new brassinosteroid analogs obtained from hyodeoxycholic acid, with a 3,6 dioxo function, 24-Nor-22(S)-hydroxy side chain and p-substituted benzoate function at C-23. The plant growth activities of these compounds were evaluated by two different bioassays: rice lamina inclination test (RLIT) and BSI. The results show that BRs' analog with p-Br (compound 41f) in the aromatic ring was the most active at 1 × 10-8 M in the RLIT and BSI assays. These results are discussed in terms of the chemical structure and nature of benzoate substituents at the para position. Electron-withdrawing and size effects seems to be the most important factor in determining activities in the RLIT assay. These results could be useful to propose a new structural requirement for bioactivity in brassinosteroid analogs.

Collective Total Synthesis of Ecklonialactones, Eiseniachlorides and Analogs.

Ecklonialactones, Eiseniachlorides, and Egregiachlorides are synthesized in living organisms via the lipoxygenase-mediated oxidation of polyunsaturated fatty acids. Originally isolated and identified from brown seaweed (Ecklonia stolonifera, Eisenia bicyclis, and Egregia menziesii), and later replicated on milligram scale through chemical synthesis, the full biological activities of these compounds remain to be elucidated. To bridge this gap in knowledge, we propose a unified methodology to synthesize the 14-membered macrocyclic structures of Ecklonialactones, Eiseniachlorides and analogs using a versatile and convergent approach. This study delineates the synthesis of Ecklonialactone A, B, C, D, and Eiseniachlorides A and B, as well as ent-Ecklonialactone B, 16-epi-Ecklonialactone B and 12,13-diepi-Ecklonialactone B.

Sulfone Electrophiles in Cross-Electrophile Coupling: Nickel-Catalyzed Difluoromethylation of Aryl Bromides.

Fluoroalkyl fragments have played a critical role in the design of pharmaceutical and agrochemical molecules in recent years due to the enhanced biological properties of fluorinated molecules compared to their non-fluorinated analogues. Despite the potential advantages conferred by incorporating a difluoromethyl group in organic compounds, industrial adoption of difluoromethylation methods lags behind fluorination and trifluoromethylation. This is due in part to challenges in applying common difluoromethyl sources towards industrial applications. We report here the nickel-catalyzed cross-electrophile coupling of (hetero)aryl bromides with difluoromethyl 2-pyridyl sulfone, a sustainably sourced, crystalline difluoromethylation reagent. The scope of this reaction is demonstrated with 24 examples (67 ± 16% average yield) including a diverse array of heteroaryl bromides and precursors to difluoromethyl-containing preclinical pharmaceuticals. This reaction can be applied to small-scale parallel synthesis and benchtop scale-up under mild conditions. As sulfone reagents are uncommon electrophiles in cross-electrophile coupling, the mechanism of this process was investigated. Studies confirmed the formation of •CF2H instead of difluorocarbene. A series of modified difluoromethyl sulfones revealed that sulfone reactivity does not correlate exclusively with reduction potential and that coordination of cations or nickel to the pyridyl group is essential to reactivity, setting out parameters for matching the reactivity of sulfones in cross-electrophile coupling.

Synthesis and anti-leishmanial activities of uniflorol analogues

AbstractChromanones are a subset of the benzopyran family, and display diverse biological activities, both as natural products and synthetic derivatives. Among these, we selected the natural product uniflorol, a 4-chromanone with an α,β-unsaturated ketone side chain, as a lead compound due to its reported anti-leishmanial properties. We designed and synthesised four series of novel compounds, varying the substitution patterns around the benzopyran core, and evaluated the compounds for anti-leishmanial activity against amastigotes of L. infantum. We prepared and characterised 24 novel compounds; upon screening, 12 compounds demonstrated activity values of <50 μM, with the most potent compound, 16d, having an IC50 of 7.29 μM. Activity was favoured in compounds bearing a phenylalkenyl motif, such as cinnamyl, styryl or a more lipophilic extension, and amide analogues retained activity. Uniflorol analogues display promise as novel architectures towards the development of potential anti-leishmanial agents.

Synthesis, antimicrobial evaluation, and molecular docking studies of Mannich base analogs derived from 2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione scaffold

Synthesis, antimicrobial evaluation, and molecular docking studies of Mannich base analogs derived from 2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione scaffold

Synthesis of acyclic nucleoside analogues through P(NMe2)3-Mediated regioselective N-alkylation

A novel and efficient approach for synthesizing acyclic nucleoside analogues with a side chain length of two carbon atoms has been established. It involves purines reacting with α-keto esters in a P(NMe2)3-mediated deoxygenation process, yielding the products in high yields and regioselectivities (22 examples, up to 93 % yield, up to >20:1 N9/N7 selectivities). This reaction features short reaction times, metal-free catalysis, mild reaction conditions, and broad substrate scope, all of which make it promising for practical applications.

Recent Advances in Synthetic Strategies of Piperazine & its Analogs Via Rearrangement Reactions: A Review

Abstract: In the six-membered heterocyclic compound piperazine, two nitrogen atoms are positioned within the ring at 1 and 4 positions. Numerous studies have shown that piperazine has the potential to be a useful pharmacophore in many harmful pharmacological conditions such as microbiocidal, antiinflammatory, anticancer, antioxidant, etc. In this present review, we highlighted the synthetic protocols for piperazine and its analogs, as well as the synthetic protocol for piperazine via rearrangement reaction, which have been adopted in recent years. The study also involved a listing of several patents (granted), which comprised important work on piperazine and its derivatives. Among all the methods, the most commonly adopted synthetic methods included the synthesis of piperazine analogs by dizacope, hydrolytic, mumm, multi-component, ugi-smiles, [2+3]-stevens, aza-Wittig, Curtius, Schmidt rearrangement reactions, etc. These synthetic protocols have also been compared based on different reaction conditions, feasibility, and economy to help the researchers in designing their work.

The Antimicrobial Peptide Capitellacin: Chemical Synthesis of Analogues to Probe the Role of Disulphide Bridges and Their Replacement with Vinyl Sulphides.

Capitellacin (1) is a 20-residue antimicrobial β-hairpin, produced by the marine polychaeta (segmented worms) Capitella teletai. Since its discovery in 2020, only very limited studies have been undertaken to understand capitellacin's structure-activity relationship (SAR). Using fast-flow Fmoc-SPPS, a focused library of capitellacin analogues was prepared to systematically study the influence of the two disulphide bridges on its structure and activity, and their replacement with a vinyl sulphide as a potential bioisostere. Upon studying the resulting peptides' antimicrobial activity and secondary structure, the most terminal disulphide emerged as the most critical element for maintaining both bioactivity and the secondary structure, properties which were demonstrated to be closely interlinked. The removal of the innermost disulphide bridge or disulphide replacement with a vinyl sulphide emerged as strategies with which to tune the activity spectrum, producing selectivity towards E. coli. Additionally, an enantiomeric d-capitellacin analogue revealed mechanistic insights, suggesting that chirality may be an inherent property of capitellacin's bacterial membrane target, or that a hitherto unknown secondary mechanism of action may exist. Additionally, we propose the Alloc protecting group as a more appropriate alternative to the common Dde group during fast-flow Fmoc-SPPS, in particular for short-chain diamino acids.

Insight into the Synthesis, Biological Activity, and Structure-activity Relationship of 1,2,4-Oxadiazole and Analogs: A Comprehensive Review

Abstract: A five-membered heterocyclic compound known as 1,2,4-oxadiazole has one oxygen, two carbon, and two nitrogen atoms within a ring. Numerous studies have shown that 1,2,4-oxadiazole has the potential to be an essential moiety in many harmful pharmacological conditions. 1,2,4-oxadiazole and its derivatives have been used as an antiviral, cough suppressant, vasodilator, anxiolytic, etc. To synthesize a single molecule with potent pharmacological action, two or more pharmacophores are combined currently. This enhances pharmacological effects, facilitates interaction possible with many targets, and reduces the adverse effects related to them. It has been reported that synthesis of 1,2,4-oxadiazole and its analog is possible using a variety of methods. In this present review, we emphasized recently accepted synthetic methods for 1,2,4-oxadiazole and its analogs synthesis. Additionally, the structure-activity relationship concerning several pharmacological effects, interactions with various targets, and the utility of different techniques for the analysis and purification has been described. On the behalf of the above study, the researchers can use this review study to better understand their 1,2,4-oxadiazole research in the future.

Synthesis, biological screening, and binding mode analysis of some N-substituted tetrahydroquinoline analogs as apoptosis inducers and anticancer agents

One of the most common malignancies in the world is lung cancer. Lung cancer involves mutations in many different genes, however, EGFR, KRAS, PTEN, and PIK3CA involvement is more frequent. The lack of effective drugs and drug resistance are major issues and obstacles associated with the current treatment of lung cancer. Seven novel tetrahydroquinoline analogs were synthesized and screened against a range of cancer cell lines in this study. Among these, 17f (IC50=0.082 µM) was shown to be the most potent when compared to the standard drug 5-Flurouracil (5FU) (IC50=0.28 µM). Moreover, flow cytometry analysis was carried out to ascertain the nature of programmed cell death. This provides conclusive evidence of late apoptosis in all synthesized compounds when contrasted with the standard drug (5FU) and control. After comparing all of the outputs, additional binding mode analysis was carried out to determine the potential mechanism of its anticancer activity. Molecular docking and MD simulation studies were carried out, and the results show that all of the synthesized compounds 17-a-f (17f docking score -10.5 Kcal/mol) have a better binding affinity towards mTOR (PDB id: 4JT6) than both the standard drug 5FU and the co-crystal ligand X6K (docking score: -7.6 Kcal/mol). Despite the aforementioned information, strong hit compounds from this series may eventually be developed to become lead mTOR inhibitors for the treatment of lung cancer.

Design and development of a novel Co‐MOF catalyst for sustainable pyrimidine synthesis via the Biginelli reaction

In this study, we introduce a novel porous metal–organic framework named Co2(bbda)2(DMF)2·5H2O, or MOF‐UoR‐1, synthesized via hydrothermal techniques employing a unique Schiff base ligand. The framework underwent comprehensive characterization, confirming its microporous nature through gas‐sorption measurements. MOF‐UoR‐1 demonstrated remarkable efficacy as a catalyst for the one‐step synthesis of pyrimidine analogs. Structural validation of the synthesized pyrimidines was accomplished via 1H‐nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) analyses. Through systematic experimentation, the optimal catalyst dosage (40 mg) was determined, showcasing its effectiveness across various aldehydes, 1,3‐carbonyl compounds, and urea substrates. Noteworthy is the broad applicability of this environmentally friendly protocol, which offers advantages such as high yields (96%), rapid reaction times (90 min), straightforward product isolation, and product purity without necessitating column chromatography. Furthermore, the catalytic integrity of the framework remained intact, enabling its reuse without compromising performance. This research presents a promising approach for the synthesis of pyrimidine derivatives, with significant implications for sustainable and efficient chemical synthesis methodologies.

Synthesis of Analog of Bistetrahydroisoquinoline Alkaloids Based on N-Homoveratrylmaleimide

Synthesis of Analog of Bistetrahydroisoquinoline Alkaloids Based on N-Homoveratrylmaleimide

Computer-aided rational design and synthesis of new potential antihypertensive agents among 1,2,3-triazole-containing nifedipine analogs

1,2,3-Triazole-containing Nifedipine analogues offer the opportunity to increase biostability, bioavailability, efficacy and binding selectivity to target receptors. Here, we applied a computer-aided rational design for identifying new Nifedipine analogues containing a 1,2,3-triazole moiety. First, a new chemical library of 796 derivatives combining the DHP fragment and 1,2,3-triazole moiety was generated. Second, to reduce the library size, the library was pre-filtered using two 3D-pharmacophore models with different complexity, which allowed us to gradually reduce the chemical space, ending up with 26 hit candidates. Molecular docking calculations against the rCav1.1 receptor allowed the identification of eight derivatives 5a-h, characterized by the binding affinity towards the rCav1.1 receptor of the same level as approved Nifedipine-like drugs. Next, our molecular docking results were used to guide and optimize the retrosynthetic approaches for new analogues of Nifedipine as promising antihypertensive agents. So, a retrosynthetic approach for Nifedipine analogues with a 1,2,3-triazole ring in position 4 was proposed. Finally, eight analogues 5a-h determined by molecular docking calculations were synthesized using the suggested retrosynthetic approach. The aim of this study is to identify new Nifedipine analogues using a computer-aided drug design and a retrosynthetic approach. Materials and Methods. The organic synthesis of new Nifedipine analogues containing a 1,2,3-triazole moiety. Computer-aided drug design of new DHP derivatives using pharmacophore screening and molecular docking calculations. Results. Molecular docking of new Nifedipine analogues made it possible to estimate the binding affinity of new Nifedipine derivatives to the rCav1.1 receptor. Pharmacophore screening of a chemical library of analogues, consisting of 796 derivatives, allowed gradually reducing the chemical space and obtaining 26 candidates with high affinity to the rCav1.1 receptor. Using the method of molecular docking, eight hits 5a-h were identified, and the synthesis of the recommended compounds was proposed and performed. Conclusions. The results of molecular docking showed that Nifedipine analogues are characterized by binding affinity to the rCav1.1 receptor at the same level as approved Nifedipine-like drugs. Pharmacophore screening and molecular docking calculations indicate key features of the ligand-receptor interaction that can guide and optimize the synthesis of new Nifedipine analogues as promising new antihypertensive agents. A retrosynthetic approach was proposed, and the recommended compounds were synthesized

Synthesis of benzhydrol analogues based on 1´-acetoxychavicol acetate (ACA), as a stable and potent antiproliferative agent on breast cancer cell lines, ADMET analysis and molecular docking study.

Synthesis of benzhydrol analogues based on 1´-acetoxychavicol acetate (ACA), as a stable and potent antiproliferative agent on breast cancer cell lines, ADMET analysis and molecular docking study.

A Bicyclic Analog of the Linear Peptide Arodyn Is a Potent and Selective Kappa Opioid Receptor Antagonist.

Kappa opioid receptor (KOR) antagonists have potential therapeutic applications in the treatment of stress-induced relapse to substance abuse and mood disorders. The dynorphin A analog arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]dynorphin A-(1-11)-NH2) exhibits potent and selective kappa opioid receptor antagonism. Multiple cyclizations in longer peptides, such as dynorphin and its analogs, can extend the conformational constraint to additional regions of the peptide beyond what is typically constrained by a single cyclization. Here, we report the design, synthesis, and pharmacological evaluation of a bicyclic arodyn analog with two constraints in the opioid peptide sequence. The peptide, designed based on structure-activity relationships of monocyclic arodyn analogs, was synthesized by solid-phase peptide synthesis and cyclized by sequential ring-closing metathesis (RCM) in the C- and N-terminal sequences. Molecular modeling studies suggest similar interactions of key aromatic and basic residues in the bicyclic peptide with KOR as found in the cryoEM structure of KOR-bound dynorphin, despite substantial differences in the backbone conformations of the two peptides. The bicyclic peptide's affinities at KOR and mu opioid receptors (MOR) were determined in radioligand binding assays, and its KOR antagonism was determined in the [35S]GTPγS assay in KOR-expressing cells. The bicyclic analog retains KOR affinity and selectivity (Ki = 26 nM, 97-fold selectivity over MOR) similar to arodyn and exhibits potent KOR antagonism in the dynorphin-stimulated [35S]GTPγS assay. This bicyclic peptide represents a promising advance in preparing cyclic opioid peptide ligands and opens avenues for the rational design of additional bicyclic opioid peptide analogs.

An efficient alternative to DBU in the oxathiaphospholane (OTP) method for the solid phase synthesis of P-stereodefined phosphorothioate analogs.

This study presents a modified (extended) 1,3,2-oxathiaphospholane (OTP) method for the synthesis of P-stereodefined phosphorothioate analogs in the presence of previously unused organic bases. TBD (5,7-triazabicyclo[4.4.0]dec-5-ene) and Verkade's proazaphosphatrane (2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane) are herein used for the first time as efficient organic bases compared to DBU, which is commonly used in the OTP approach.

Addressing Reproducibility Challenges in High-Throughput Photochemistry.

Light-mediated reactions have emerged as an indispensable tool in organic synthesis and drug discovery, enabling novel transformations and providing access to previously unexplored chemical space. Despite their widespread application in both academic and industrial research, the utilization of light as an energy source still encounters challenges regarding reproducibility and data robustness. Herein we present a comprehensive head-to-head comparison of commercially available batch photoreactors, alongside the introduction of the use of batch and flow photoreactors in parallel synthesis. Hence, we aim to establish a reliable and consistent platform for light-mediated reactions in high-throughput mode. Herein, we showcase the identification of several platforms aligning with the rigorous demands for efficient and robust high-throughput experimentation screenings and library synthesis.