Heterocyclic Libraries Research Articles

Synthesis and insecticidal assessment of nitrogenous heterocycles derived from 2-pyridone derivative against Culex pipiens L. Larvae

This study reports the synthesis of a novel 1,6-diamino-4-(2,4-dichlorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1) and its subsequent functionalization to yield a library of diverse heterocycles (2–10). The nucleophilicity of compound 1 was exploited to react with various electrophiles to afford a range of structurally enriched derivatives. The structures of all synthesized heterocycles were confirmed by elemental analysis and spectroscopic techniques as (FT-IR, 1H NMR, 13C NMR, and mass spectroscopy). Bioassays revealed significant larvicidal activity against mosquito larvae (Culex pipiens L.) for compounds 1–4, 6, 7 and 9. In silico docking studies suggest a potential mode of action through acetylcholinesterase (AChE) inhibition, potentially explaining the observed larvicidal effect. Additionally, interactions with other neuroreceptors were predicted. Finally, analyzing of the structure activity relationship (SAR) of the novel constructed heterocycles gave us a lot of interesting promising results for developing novel and sustainable mosquito control strategies.

Synthesis and Biological Evaluation of Novel Imidazolone - Thiabendazole-Based Metal Complexes.

Thiabendazole-based metal complexes are attracting interest due to their special antimicrobial activities. The current investigation describes the preparation of ligand L1 and its metal complexes [M (C26H17N5OS) Cl2] M = Co, Ni, Cu and Zn. Mass, 1 H-NMR, IR, and UV were used to characterize these compounds. L1 exhibited the highest potency towards many bacteria. It shows the maximum zone of inhibition as compared to any other ligand. Thus, the antibacterial potency of L1 is better as compared to standard drugs. Imidazolone-TBZ ligands L1 are also more susceptible to some bacteria and also show antifungal potency against Pseudomonas aeruginosa. The significance of such work triggered the possibility that these ligands L1 and metal complexes can be efficacious drugs against bacterial and fungal species that could be advantageous in designing powerful antibacterial and antifungal compounds for medicinal use. All these synthesized compounds are in addition to the library of heterocyclic compounds.

Tunable Regioselective Allylic Alkylation/Iodination of Imidazoheterocycles in Water.

The switchable roles of allylic alcohol and molecular iodine as reagents and catalysts have been demonstrated in the regioselective allylic alkylation and iodination of imidazoheterocycles employing the mixture of allylic alcohol-I2. First, we have explored the catalytic activity of iodine for the allylation of imidazoheterocycles using allylic alcohol in an aqueous medium. The allylation of a library of imidazoheterocycles and other electron-rich heterocycles like indole, pyrazole, 4-hydroxy coumarin, and 6-amino uracil has been achieved by employing this methodology. The efficiency of the I2 catalyst for N-allylation of azoles has also been demonstrated. Next, we have shown that this mixture of allylic alcohol and I2 could be beneficial for the iodination of imidazoheterocycles under room temperature. Mechanistic studies indicate that the activation of allylic alcohol by molecular iodine took place probably through halogen bonding, and NMR studies show that the reaction did not proceed through allylic ether formation.

In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity

The development of new antimalarials is paramount to keep the goals on reduction of malaria cases in endemic regions. The search for quality hits has been challenging as many inhibitory molecules may not progress to the next development stage. The aim of this work was to screen an in-house library of heterocyclic compounds (HCUV) for antimalarial activity combining computational predictions and phenotypic techniques to find quality hits. The physicochemical determinants, pharmacokinetic properties (ADME), and drug-likeness of HCUV were evaluated in silico, and compounds were selected for structure-based virtual screening and in vitro analysis. Seven Plasmodium target proteins were selected from the DrugBank Database, and ligands and receptors were processed using UCSF Chimera and Open Babel before being subjected to docking using Autodock Vina and Autodock 4. Growth inhibition of P. falciparum (3D7) cultures was tested by SYBR Green assays, and toxicity was assessed using hemolytic activity tests and the Galleria mellonella in vivo model. From a total of 792 compounds, 341 with good ADME properties, drug-likeness, and no interference structures were subjected to in vitro analysis. Eight compounds showed IC50 ranging from 0.175 to 0.990 µM, and active compounds included pyridyl-diaminopyrimido-diazepines, pyridyl-N-acetyl- and pyridyl-N-phenyl-pyrazoline derivatives. The most potent compound (UV802, IC50 0.178 µM) showed no toxicophoric and was predicted to interact with P. falciparum 1-cysperoxidredoxin (PfPrx1). For the remaining 7 hits (IC50 < 1 μM), 3 showed in silico binding to PfPrx1, one was predicted to bind the haloacid dehalogenase-like hydrolase and plasmepsin II, and one interacted with the plasmodial heat shock protein 90.

Benzimidazole and piperidine containing novel 1,2,3-triazole hybrids as anti-infective agents: Design, synthesis, in silico and in vitro antimicrobial efficacy.

Cu alkyne-azide cycloaddition was used to easily synthesize a library of novel heterocycles containing benzimidazole and piperidine based 1,2,3-triazole(7a-7l) derivatives. The synthesized analogs were characterized by various spectroscopic techniques like FTIR, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass spectrometry. All these novel bioactive compounds (7a-7l) were evaluated for in vitro antibacterial and antifungal efficacy. Compound 7k exhibited appreciable potent activity against Escherichia coli strain. Compounds 7a, 7b, 7f, and 7i showed excellent potent activity against all bacterial strains. Compound 7b, 7c, 7d, and 7g derivatives showed excellent effects when tested in vitro for antifungal activity against various fungal strains. Additionally, a molecular docking investigation revealed that compound 7k has the ability to bind to the active site of the E. coli DNA gyrase subunit protein and form hydrogen bonds with significant amino acid residues Asp73 and Asp49 in the active sites. In a 100 ns molecular dynamics simulation, the E. coli DNA gyrase protein's steady capacity to bind compound 7k was shown by the low measured root mean square deviation, which was an indication of the complex's conformational stability.

Heterocyclic Diaryliodonium-Based Inhibitors of Carbapenem-Resistant Acinetobacter baumannii.

Finding new therapeutic strategies against Gram-negative pathogens such as Acinetobacter baumannii is challenging. Starting from diphenyleneiodonium (dPI) salts, which are moderate Gram-positive antibacterials, we synthesized a focused heterocyclic library and found a potent inhibitor of patient-derived multidrug-resistant Acinetobacter baumannii strains that significantly reduced bacterial burden in an animal model of infection caused by carbapenem-resistant Acinetobacter baumannii (CRAB), listed as a priority 1 critical pathogen by the World Health Organization. Next, using advanced chemoproteomics platforms and activity-based protein profiling (ABPP), we identified and biochemically validated betaine aldehyde dehydrogenase (BetB), an enzyme that is involved in the metabolism and maintenance of osmolarity, as a potential target for this compound. Together, using a new class of heterocyclic iodonium salts, a potent CRAB inhibitor was identified, and our study lays the foundation for the identification of new druggable targets against this critical pathogen. IMPORTANCE Discovery of novel antibiotics targeting multidrug-resistant (MDR) pathogens such as A. baumannii is an urgent, unmet medical need. Our work has highlighted the potential of this unique scaffold to annihilate MDR A. baumannii alone and in combination with amikacin both in vitro and in animals, that too without inducing resistance. Further in depth analysis identified central metabolism to be a putative target. Taken together, these experiments lay down the foundation for effective management of infections caused due to highly MDR pathogens.

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME NOVEL5-(2- CHLOROPHENYL)-2-(METHYLTHIO)-6-NITRO-7-(2-OXO-1, 2-DIHYDROQUINOLIN-3-YL)-4, 7-DIHYDROPYRAZOLO [1,5-A]PYRIMIDINE-3-CARBONITRILE DERIVATIVES

A novel heterocyclic library was synthesized, characterized and tested for biological evaluation against bacteria and fungus. This novel series of pyrazole pyrimidine derivatives of 5-(2-chlorophenyl)-2-(methylthio)-6-nitro-7-(2-oxo-1, 2- dihydroquinolin-3-yl)-4,7-dihydropyrazolo [1,5-a]pyrimidine-3-carbonitrile in the presence of methanoland hydrochloric acid in good yield. The title compounds have been synthesized with several structural variations. The synthesized compounds were screened for antimicrobial activity against standard drugs. The structure of synthesized compounds were characterized by their spectral (IR, 1H NMR and Mass) data. The purity of the synthesized compounds was confirmed by TLC.

Discovery of 4,4'-Dipyridylsulfide Analogs as "Switchable Electrophiles" for Covalent Inhibition.

Electrophilic heterocycles offer attractive features as covalent fragments for inhibitor and probe development. A focused library of heterocycles for which protonation can enhance reactivity (called "switchable electrophiles") is screened for inhibition of the proposed drug target dimethylarginine dimethylaminohydrolase (DDAH). Several novel covalent fragments are identified: 4-chloroquinoline, 4-bromopyridazine, and 4,4-dipyridylsulfide. Mechanistic studies of DDAH inactivation by 4,4-dipyridylsulfide reveal selective covalent S-pyridinylation of the active-site Cys through catalysis by a neighboring Asp residue. Inactivation (kinact/KI = 0.33 M-1 s-1) proceeds with release of 4-thiopyridone (0.78 equiv), and structure-activity relationships reveal that the leaving group pKa can be modulated to tune reactivity. The use of a "switchable electrophile" strategy helps impart selectivity, even to fragment-sized modifiers. Identification of 4,4-dipyridylsulfide analogs as inactivators offers an easily tunable covalent fragment with multiple derivatization sites on both the leaving and staying groups.

Synthesis, Characterization and Biological Evaluation of Some Novel Substitute N-(4-(3-Oxomorpholino)phenyl)-2-(4-((phenylamino)methyl)-1H- 1,2,3-triazol-1-yl)-acetamide via Click Chemistry Approach

A novel heterocyclic library were synthesized, characterized and tested for biological evaluation against bacteria and fungus. This novel series of substitute N-(4-(3-oxomorpholino)phenyl)-2-(4- ((phenylamino)-methyl)-1H-1,2,3-triazol-1-yl)acetamide via click chemistry approach in the presence of DMF:H2O:n-BuOH and CuSO4·5H2O in good yield. The title compounds have been synthesized with several structural variations. The synthesized compounds were screened for antimicrobial activity against standard drugs. The structure of synthesized compounds characterized by their spectral (IR, 1H NMR and mass) data. The purity of the synthesized compounds was confirmed by TLC.

Drug design: 4-thiazolidinones applications. Part 2. Pharmacological profiles

Following of the chemical diversity of 4-thiazolidinones the in-house library of new heterocycles have been designed and synthesized (more 7000 compounds). Anticancer, antitrypanosomal, antituberculosis and antiviral activity screening led to SAR database formation; lead-compounds identification; design of focused sub-libraries; formation and validation of hypotheses for structure optimization: i) complications of C5 fragment and/or functionalization of N3 position; ii) creation of the hybrid molecules; iii) fixation of 5-ene-4-thiazolidinones in fused heterocycles via annulation (thiopyrano[2,3-d]thiazoles were found as a cyclic isosteric mimetics of 5-ene-4-thiazolidinones); iv) the leukemia panel was detected to be the most sensitive among all cancer cell lines. Following the in silico and pharmacological data for the investigation of molecular mechanism of anticancer effect the argument in favor of the apoptotic related and mild prooxidant actions for active compounds have been found.

Synthesis and Antibacterial Screening of Some Pyrazole Derivatives Catalyzed by Cetyltrimethylammoniumbromide (CTAB).

In this article, we have developed an eco-friendly one-pot multi-component reaction methodology employed for the green synthesis of functionalized pyrazole derivatives viz cyclo-condensation of aromatic aldehydes, ethyl acetoacetate and phenyl hydrazine and/or hydrazine hydrate in the presence of cetyltrimethylammoniumbromide (CTAB) at 90°C temperature in an aqueous medium. In the present protocol, we developed a green method for the synthesis of functionalized pyrazole derivatives through one-pot, multi-component cyclo-condensation of aromatic aldehydes, phenyl hydrazine or hydrazine hydrate and ethyl acetoacetate using cetyltrimethylammoniumbromide (CTAB) as a catalyst in water as a solvent. Our methodology confers advantages such as short reaction time, atom economy, purification of the product without using column chromatographic and hazardous solvent. The reaction is being catalyzed by cetyltrimethylammoniumbromide (CTAB) and thus, products are formed under the green reaction conditions. Initially, the reaction of benzaldehyde and phenylhydrazine with ethyl acetoacetate was carried out in water at room temperature in the absence of the catalyst; no product was obtained after 24 h (Table 1 entry 1). When the reaction was carried out using L-proline as a catalyst in ethanol at 70°C, the yield of the product was 20%. This research not only provides a green and efficient method for the synthesis of sulfinic esters but also shows new applications of electrochemistry in organic synthesis. We consider that this green and efficient synthetic protocol used to prepare sulfinic esters will have good applications in the future. In conclusion, we have developed successfully a green and efficient one-pot multi-component methodology for the synthesis of substituted pyrazoles using CTAB as a catalyst in water as a solvent with excellent yields. Purifications of compounds were achieved without the use of traditional chromatographic procedures. This methodology has advantages of operational simplicity, clean reaction profiles and relatively broad scope, which make it more attractive for the diversity oriented synthesis of these heterocyclic libraries. In this methodology, we suggest a further alternative possibility for the formation of substituted pyrazoles. The compound 7h can be used as an anticancer drug in the pharma industry.

Recent developments in synthetic chemistry and biological activities of pyrazole derivatives

Pyrazole, a five-membered heterocycle containing two nitrogen atoms, is extensively found as a core framework in a huge library of heterocyclic compounds that envelops promising agro-chemical, fluorescent and biological potencies. Attributed to its several potential applications, there is a rise in the significance of designing novel pyrazoles, disclosing innovative routes for synthesizing pyrazoles, examining different potencies of pyrazoles, and seeking for potential applications of pyrazoles. This review consists of two parts. The first part provides an overview on the recent developments in synthetic approaches to pyrazoles, which is related to the new or advanced catalysts and other ‘environment-friendly’ procedures, including heterogeneous catalytic systems, ligand-free systems, ultrasound and microwave-assisted reactions. The second part focuses on the recently reported novel biological affinities of pyrazoles. This systematic review covers the published studies from 1990 to date. It is expected that this review will be helpful in future research and for new thoughts in the quest for rational designs for developing more promising pyrazoles. The review consists of two parts: (i) an overview on the recent advances in synthetic approaches for the preparation of pyrazoles, including eco-friendly methodologies, heterogeneous catalytic systems, ligand-free systems, ultrasound and microwave-assisted reactions, and (ii) a summary of recently reported novel biological affinities of pyrazoles.

Synthesis of Benzofurans and Benzoxazoles through a [3,3]-Sigmatropic Rearrangement: O–NHAc as a Multitasking Functional Group

The synthesis of heterocycles relies heavily on diverse sigmatropic rearrangements triggered by the cleavage of X–Y (X, Y = C, O, N, S, I) bonds. However, a unified rearrangement approach for constructing heterocyclic libraries is highly desirable. Encouraged by computational analysis of [3,3]-sigmatropic rearrangements, we can now rapidly synthesize oxa-heterocycles by treating N-phenoxyacetamides (Ph–ONHAc) with compounds containing an sp-hybridized carbon. The generality of the process is illustrated by the late-stage diversification of natural products, including estrone and an approved drug. A combination of experimental and computational studies revealed that the reactions proceed through a facile Claisen-like [3,3]-sigmatropic rearrangement/annulation process.

Design and characterization of a heterocyclic electrophilic fragment library for the discovery of cysteine-targeted covalent inhibitors.

A fragment library of electrophilic small heterocycles was characterized through cysteine-reactivity and aqueous stability tests that suggested their potential as covalent warheads. The analysis of theoretical and experimental descriptors revealed correlations between the electronic properties of the heterocyclic cores and their reactivity against GSH that are helpful in identifying suitable fragments for cysteines with specific nucleophilicity. The most important advantage of these fragments is that they show only minimal structural differences from non-electrophilic counterparts. Therefore, they could be used effectively in the design of targeted covalent inhibitors with minimal influence on key non-covalent interactions.

Heterocyclic electrophiles as new MurA inhibitors.

An electrophilic fragment library of small heterocycles was developed and characterized in the surrogate GSH-reactivity assay and aqueous stability test that revealed their potential as covalent warheads. Screening the library against MurA from Staphylococcus aureus (MurASA ) and Escherichia coli (MurAEC ) identified heterocyclic fragments with significant inhibitory potency. The validated heterocyclic warhead library might be useful for developing targeted covalent inhibitors for other targets of interest with a new design strategy incorporating heterocyclic electrophiles as warheads.

‘Heteroaromatic Rings of the Future’: Exploration of Unconquered Chemical Space

William Pitt and co-workers have created a virtual exploratory heterocyclic library ‘VEHICLe’ containing over 200 unconquered bicyclic heteroaromatic rings, synthetically feasible with potential medicinal interest. Since the publication of the 22 ‘heteroaromatic rings of the future’ by Pitt in 2009, 15 of them have been successfully synthesized as bicyclic or polycyclic forms and evaluated for applications in both biology and material science. This short review presents the critical synthesis associated with innovative synthetic methodologies of the synthetically conquered ring scaffolds from the list of 22 with a spotlight on the scientific contribution of this fascinating article for the expansion of the chemical diversity.1 Introduction2 Heteroaromatic Rings of the Future: The Synthetic challenge?2.1 4-Pyrido[1,3]oxazin-4-one-P1 2.2 Pyrrolo[2,1-b][1,3]oxazin-4-one-P4 2.3 Furo[2,1-e]pyridazin-4(1H)-one-P5 2.4 Isoxazolo[3,4-c]pyridin-7-one-P6 2.5 5H,6H-[1,2]Thiazolo[5,4-c]pyridin-5-one-P7 2.6 4H,5H-Furo[3,2-b]pyridin-5-one-P8 2.7 1H,5H,6H-Pyrazolo[3,4-c]pyridin-5-one-P9 2.8 Thieno[3,4-c]pyridazine-P10 2.9 Pyrrolo[1,2-c][1,2,3]triazine-P11 2.10 Thieno[3,4-a]oxazole-P12 2.11 2,4-Dihydropyrrolo[3,2-c]pyrazole-P13 2.12 Pyrazolo[1,5-b]isoxazole-P14 2.13 Imidazo[1,5-c]pyrimidin-3(2H)-one-P16 2.14 Cyclopenta[b][1,4]oxazin-5(4H)-one-P17 2.15 2,3-Dihydro-2,6-naphthyridin-3-one-P18 3 Conclusion

Multi-Gram Synthesis of Enantiopure 1,5-Disubstituted Tetrazoles Via Ugi-Azide 3-Component Reaction.

Tetrazoles have been widely studied for their biological properties. An efficient route for large-scale synthesis of 1,5-disubstituted tetrazoles (1,5-DTs) is presented. The strategy exploits a reductive approach to synthetize a cyclic chiral imine substrate which is then converted into the target product through an Ugi-azide three-component reaction (UA-3CR). The final products are equipped with additional functionalities which can be further elaborated for the generation of combinatorial libraries of enantiopure heterocycles.

Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria

Bacterial resistance to polymyxin antibiotics has taken on a new and more menacing form. Common are genomically-encoded resistance mechanisms to polymyxins, specifically colistin (polymyxin E), however, the plasmid-borne mobile colistin resistance-1 (mcr-1) gene has recently been identified and poses a new threat to global public health. Within six months of initial identification in Chinese swine in November 2015, the first human clinical isolation in the US was reported (Apr. 2016). Herein we report successful reversion of mcr-1-driven colistin resistance in Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli with adjuvants we previously reported as modulators of chromosomally-encoded colistin resistance. Further screening of our in-house library of nitrogen-dense heterocycles has identified additional chemical scaffolds that actively attenuate colistin resistance. Ultimately, we present a diverse cohort of adjuvants that both sensitize colistin-resistant and colistin-susceptible bacteria to this antibiotic, thus providing a potential avenue to both reduce colistin dosage and toxicity, and overcome colistin resistance.

Synthesis of Highly Z‐Selective Coumarin Annulated Dioxocine, Dioxacindione and Macrocycles Using Grubbs’ Second‐Generation Catalyst

AbstractThe diversity‐oriented organic synthesis of novel coumarin annulated tricyclic dioxocine, dioxacindione scaffolds with Z‐selectivity and the symmetrical pentacyclic coumarin macrocyclic derivatives is demonstrated from substituted hydroxyl coumarins via ring‐closing metathesis in the presence of Grubbs’ second‐generation catalyst as the facile and efficient route with excellent yields. This synthetic strategy provides a route for the intramolecular ring‐closing metathesis to access a library of novel tricyclic coumarin heterocycles and pentacyclic coumarin macrocycles having different ring systems.

Efficient Lactic Acid-catalyzed Route to Naphthopyranopyrimidines under Solvent-free Conditions

Multi-component reactions (MCRs) are pivotal because of their versatility for the generation of interesting heterocyclic scaffolds and libraries of biologically active molecules. They have several ...