Methods Of Organic Chemistry Research Articles

Recent Advances in Radical Reactions of 1,n‐Enynes with Phosphorus‐Centered Radicals

AbstractOrganophosphorus compounds have been widely used as achiral and chiral ligands in organic synthesis (PPh3, BINAP, dppe, Duphos, Xantphos, PPFA, Chiraphos, SEGPHOS), flame retardants, functional materials (LED, PV), as well as agrochemicals and medicines due to their broad biological activities. As the privileged versatile building blocks, 1,n‐enynes have been successfully applied in the synthesis of various functionalized cyclic compounds based on their two active unsaturated chemical bonds (C═C double and C≡C triple bonds). With the development of highly selective and efficient methods in organic chemistry, various organophosphorus cyclic compounds synthesis through radical cascade strategy has attracted considerable attention in recent years. In here, we have summarized the recent main achievements in the radical cascade reactions of 1,n‐enynes with phosphorus‐centered radicals. Furthermore, we also displayed the detailed reaction mechanisms in this review.

Some transformations in a series of 4-amino-1,2,4-triazole-3-thion derivatives

The continuous improvement of synthesis methods enables the optimization of the process for developing and obtaining target products of chemical transformation. Derivatives of 1,2,4-triazole-3-thiol present a convenient object for chemical transformation, facilitating the creation of promising biologically active compounds. Combining the structure of this heterocyclic system with pharmacophore fragments of different natures allows for more effective work on the development of molecules with high pharmacological potential. To implement this strategy, 2-,3-,4-fluorophenyl-4-amino-1,2,4-triazol-3-thiones were utilized as starting structures. This molecule possesses three reaction centers, facilitating a wide range of chemical transformations involving these substances. The aim of the work was to create a series of 4-amino-2-((R1,R2-amino)methyl)-5-((2-,3-,4)-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones as a promising source for the preparation of biologically active substances. Materials and methods. The structure of the target compounds has been formed using well-known methods of organic chemistry. The starting materials used were 2-,3-,4-fluorophenyl-4-amino-1,2,4-triazol-3-thiones, which were previously obtained. The first stage of the work involved the temporary protection of the amino group with a tert-butoxycarbonyl group. The second stage of the work involved the realization of Mannich reactions involving primary and secondary amines. The reaction has been carried out with formalin in an alcohol-dioxane medium. The products of the chemical transformation have been recrystallized in methanol. The third stage of the work was based on the removal of Boc-protection, which was realized using hydrochloric acid in a dioxane medium. The structures of all synthesized substances have been determined by 1H NMR spectroscopy and elemental analysis. The individuality of the compounds has been confirmed by high-performance liquid chromatography. Results. The successful study of the mechanisms of Mannich reactions for 4-amino-1,2,4-triazole-3-thione derivatives allowed us to obtain 4-amino-2-((R1,R2-amino)methyl)-5-((2-,3-,4)-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones in quantitative yields. The studies made it possible to establish the favorable effect of protecting the amino group of the 2-,3-,4-fluorophenyl-4-amino-1,2,4-triazole-3-thione of the tert-butyloxycarbonyl group on the course and direction of the reaction. Conclusions. The optimal conditions for the Mannich reactions involving 2-,3-,4-fluorophenyl-4-amino-1,2,4-triazole-3-thione with intermediate Boc-protection of the amino group have been determined, which allowed us to create the theoretical basis for the successful use of Mannich reactions to expand the range of promising 4-amino-1,2,4-triazole-3-thione derivatives.

Recent advances in research on sample pretreatment methods based on supramolecular-derived porous organic polymers

Porous organic polymers (POPs) are a class of materials composed of organic building blocks usually consisting of the elements C, H, O, N, and B and other light elements connected by covalent bonds. Owing to the diversity of synthesis methods in organic chemistry, POPs can be prepared by Suzuki coupling, Sonogashira-Hagihara cross-coupling, Schiff-base condensation, Knoevenagel condensation, and Friedel-Crafts alkylation. POPs show great application potential in the field of sample pretreatment because of their large specific surface area, adjustable pore size, high tailorability, and easy modification. The design of new functional building blocks is an important factor in advancing the development of POPs and is key to the efficient separation and enrichment of target molecules in complex substrates. In recent years, supramolecular-derived compounds have provided new inspiration and breakthroughs in the construction of POPs on account of their excellent host-guest recognition properties, simple functionalization strategies, and adjustable topological configurations. The "cavitand-to-framework" approach, that is, the knitting of 0D macrocycles into hierarchical 2D or 3D POPs using suitable linkers, and extension of the research scope of supramolecular chemistry from discrete cavities to rigidly layered porous organic frameworks can lead to significant improvements in the porosity and stability of supramolecular-derived compounds. They can also provide an effective means to expand the structural diversity of POPs and generate layered structures with high porosity. This review summarizes the preparation strategies and structural characteristics of supramolecular-derived POPs with different structures, such as crown ether-based POPs, cyclodextrin-based POPs, and calixarene-based POPs. The promising applications of these materials in sample pretreatment focusing on food analysis and environmental monitoring, including epoxides, organic dyes, heavy metals, algatoxins, halogens, and antibiotic drugs, are then summarized. Next, the extraction mechanisms mainly attributed to host-guest recognition, π-π stacking, and hydrogen-bonding and electrostatic interactions between the supramolecular structures and analytes are described. The key role and potential advantages of the different preparation strategies and structural characteristics of these POPs in sample pretreatment are also discussed. Finally, the future prospects and remaining challenges of supramolecular-derived POPs are proposed. Supramolecular-derived POPs can not only achieve the rapid and selective extraction of target analytes during sample pretreatment but also improve the extraction effect of online solid phase extraction technologies. However, although numerous supramolecular-derived POPs have been developed, few have been applied in the field of sample pretreatment. Thus, the expansion of the application potential of more POP materials requires further exploration and research. The design and synthesis of supramolecular-derived POPs with highly selective recognition performance remains an important research direction in the field of sample pretreatment.

A highly efficient N-rich Cu-MOF heterogeneous catalyst based on N,N-bis(1H-tetrazole- 5-yl)amine for the A3 coupling reaction

The preparation of propargylamines using metal-organic frameworks (MOFs) with high yields in short reaction times is a new method in organic chemistry. A N-rich Cu-MOF catalyst, [Cu(BTA)2]n, with N,N-bis(1(2)H-tetrazol-5-yl)amine (BTA) ligand has been prepared and characterized using FT-IR, XRD, SEM, EDX, and ICP-AES techniques to investigate its performance as a recyclable catalyst in aldehyde-alkyne-amine (A3) coupling reaction for the synthesis of propargylamine derivatives. This catalytic system offers various advantages such as simplicity, high efficiency, short reaction time, and environmental friendliness.

Recent Advances in the Electrochemical Defluorinative Transformations of C—F Bonds

Comprehensive SummaryOrganic fluorine compounds are ubiquitous and pivotally important organic molecules, yet their activation and transformation have long been a formidable challenge due to the high energy and low reactivity of C—F bonds. Organic electrosynthesis, an environmentally benign synthetic method in organic chemistry, enables a myriad of chemical transformations without the need for external redox reagents. In recent years, organic electrochemistry has emerged as a powerful tool for achieving the activation and transformation of C—F bonds in fluorine‐containing compounds. This review aims to succinctly recapitulate the latest advancements in the electrochemical defluorinative transformations of C—F bonds and to delve into the reaction design, mechanistic insights, and developmental prospects of these methods. Key ScientistsIn 1959, Lund was the first to pioneer the electroreduction of CF3 to CH3 group. Electrochemistry has lately provided new opportunities for efficient conversion of organic fluorides. In 2020, Zhou and coworkers discovered the electrochemical defluorinative carboxylation of α‐CF3 alkenes. Lambert and colleagues reported electrophotocatalytic defluorinative amination of aryl fluorides. Electrochemical hydrodefluorination of trifluoromethylketones was developed by Lennox and coworkers in 2021. In the same year, Wang and Guo disclosed electrochemical radical defluorinative alkylation of α‐CF3 alkenes with Katritzky salts as the alkyl radical precursors. Subsequently, Wu and Liao described a transition‐metal‐free, site‐selective C—F arylation of polyfluoroarenes with (het)arenes using paired electrophotocatalysis. In 2023, numerous efforts were made to achieve electrochemical C—F bond activation. Xia and Guo developed an organoboron‐controlled method for the chemoselective electrochemical sequential (deutero)hydrodefluorination of trifluoroacetamides.

Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives - Imidazoline Receptor Agonists.

The paper presents the results of a study on the first synthesized benzimidazole derivatives obtained from labile nature carboxylic acids. The synthesis conditions of these substances were studied, their structure was proved, and some components were found to have sugar-reducing activity on the model of alloxan diabetes in rats. The study used molecular modeling methods such as docking based on the evolutionary model (igemdock), RP_HPLC method to monitor the synthesis reaction, and 1H NMR and 13C NMR, and other methods of organic chemistry to confirm the structures of synthesized substances. The docking showed that the ursodeoxycholic acid benzimidazole derivatives have high tropics to all imidazoline receptor carriers (PDB ID: 2XCG, 2bk3, 3p0c, 1QH4). The ursodeoxycholic acid benzimidazole derivative and arginine and histidine benzimidazole derivatives showed the highest sugar-lowering activity in the experiment on alloxan-diabetic rats. For these derivatives, the difference in glucose levels of treated rats was significant against untreated control. Therefore, the new derivatives of benzimidazole and labile natural organic acids can be used to create new classes of imidazoline receptor inhibitors for the treatment of diabetes mellitus and hypertension.

Recent Developments and Applications of Biocatalytic and Chemoenzymatic Synthesis for the Generation of Diverse Classes of Drugs.

Biocatalytic and chemoenzymatic biosynthesis are powerful methods of organic chemistry that use enzymes to execute selective reactions and allow the efficient production of organic compounds. The advantages of these approaches include high selectivity, mild reaction conditions, and the ability to work with complex substrates. The utilization of chemoenzymatic techniques for the synthesis of complicated compounds has lately increased dramatically in the area of organic chemistry. Biocatalytic technologies and modern synthetic methods are utilized synergistically in a multi-step approach to a target molecule under this paradigm. Chemoenzymatic techniques are promising for simplifying access to essential bioactive compounds because of the remarkable regio- and stereoselectivity of enzymatic transformations and the reaction diversity of modern organic chemistry. Enzyme kits may include ready-to-use, reproducible biocatalysts. Its use opens up new avenues for the synthesis of active therapeutic compounds and aids in drug development by synthesizing active components to construct scaffolds in a targeted and preparative manner. This study summarizes current breakthroughs as well as notable instances of biocatalytic and chemoenzymatic synthesis. To assist organic chemists in the use of enzymes for synthetic applications, it also provides some basic guidelines for selecting the most appropriate enzyme for a targeted reaction while keeping aspects like cofactor requirement, solvent tolerance, use of whole cell or isolated enzymes, and commercial availability in mind.

A Review on the Use of Deep Eutectic Solvents in Protection Reactions.

Given the recent research on the application of eco-sustainable methods in organic chemistry, we have focused our attention on the derivatization processes for fundamental functional groups in organic chemistry, such as amino, hydroxyl and carbonyl groups. Protection reactions are needed to temporarily block a certain reactive site on a molecule. The use of green solvents in this context has made an excellent contribution to the development of eco-sustainable methods. In recent years, deep eutectic solvents (DESs) have had great success as a new class of green solvents used in various chemical applications, such as extraction or synthetic processes. These solvents are biodegradable and nontoxic. In this framework, a list of relevant works found in the literature is described, considering DESs to be a good alternative to classic toxic solvents in the protection reactions of important functional groups.

Enzymatic Catalysts for Hydroxamic Acid Formation: A Mini‐Review

AbstractIn recent years, biocatalysts have emerged as crucial tool in organic synthesis, particularly for the production of drug intermediates and precursors, e.g., the synthesis of hydroxamic acids. Traditionally, hydroxamic acids were synthesized using organic chemistry methods. However, with the growing emphasis on sustainable and environment‐friendly practices, the chemical industry has increasingly turned towards green synthesis approaches. The significance of hydroxamic acids in medicinal chemistry has also contributed to the changing trends. Following the approval of certain hydroxamic acids as histone deacetylase (HDAC) inhibitors for cancer treatment by the Food and Drug Administration (US‐FDA), there has been a renewed focus on their synthesis and the development of derivatives with improved properties. As an alternative route, amidases have emerged as promising biocatalysts for hydroxamic acid synthesis through their acyltransferase activity. Recent advancements in the synthesis approaches for hydroxamic acids are reviewed. The biocatalytic routes are explored, emphasizing the use of amidases and their acyltransferase activity. The scope and potential applications of this chemoenzymatic approach in synthesizing various hydroxamic acids and their derivatives are discussed. Such advancements have the potential to revolutionize the production of these important compounds, making the synthesis process more sustainable, efficient, and economically viable.

Synthesis and anthelmintic activity of novel thiosemicarbazide and 1,2,4-triazole derivatives: In vitro, in vivo, and in silico study

IntroductionIntestinal parasitic infections are neglected diseases and, due to the increasing resistance of parasites to available drugs, they pose an increasing therapeutic challenge. Therefore, there is a great need for finding new compounds with antiparasitic activity. Objectives: In this work, new thiosemicarbazide and 1,2,4-triazole derivatives were synthesized and tested for their anthelmintic activity. MethodsThe synthesis was carried out by classical methods of organic chemistry. Anthelmintic activity tests were carried out in vitro (Rhabditis sp., Haemonchus contortus, Strongylidae sp.) in vivo (Heligmosomoides polygyrus/bakeri), and in silico analysis was performed. ResultsQuinoline-6-carboxylic acid derivative compounds were designed and synthesized. The highest activity in the screening tests in the Rhabditis model was demonstrated by compound II-1 with a methoxyphenyl substituent LC50 = 0.3 mg/mL. In the next stage of the research, compound II-1 was analyzed in the H. contortus model. The results showed that compound II-1 was active and had ovicidal (percentage of dead eggs > 45 %) and larvicidal (percentage of dead larvae > 75 %) properties. Studies in the Strongylidae sp. model confirmed the ovicidal activity of compound II-1 (percentage of dead eggs ≥ 55 %). In vivo studies conducted in the H. polygyrus/bakeri nematode model showed that the number of nematodes decreased by an average of 30 % under the influence of compound II-1. In silico studies have shown two possible modes of action of compound II-1, i.e. inhibition of tubulin polymerization and SDH. The test compound did not show any systemic toxic effects. Its influence on drug metabolism related to the activity of cytochrome CYP450 enzymes was also investigated. ConclusionThe results obtained in the in vitro, in vivo, and in silico studies indicate that the test compound can be described as a HIT, which in the future may be used in the treatment of parasitic diseases in humans and animals.

Time-resolved imaging and analysis of the electron beam-induced formation of an open-cage metallo-azafullerene.

The visualization of single-molecule reactions provides crucial insights into chemical processes, and the ability to do so has grown with the advances in high-resolution transmission electron microscopy. There is currently a limited mechanistic understanding of chemical reactions under the electron beam. However, such reactions may enable synthetic methodologies that cannot be accessed by traditional organic chemistry methods. Here we demonstrate the synthetic use of the electron beam, by in-depth single-molecule, atomic-resolution, time-resolved transmission electron microscopy studies, in inducing the formation of a doubly holed fullerene-porphyrin cage structure from a well-defined benzoporphyrin precursor deposited on graphene. Through real-time imaging, we analyse the hybrid's ability to host up to two Pb atoms, and subsequently probe the dynamics of the Pb-Pb binding motif in this exotic metallo-organic cage structure. Through simulation, we conclude that the secondary electrons, which accumulate in the periphery of the irradiated area, can also initiate chemical reactions. Consequently, designing advanced carbon nanostructures by electron-beam lithography will depend on the understanding and limitations of molecular radiation chemistry.

Cross- and Multi-Coupling Reactions Using Monofluoroalkanes.

Carbon-fluorine bonds are stable and have demonstrated sluggishness against various chemical manipulations. However, selective transformations of C-F bonds can be achieved by developing appropriate conditions as useful synthetic methods in organic chemistry. This review focuses on C-C bond formation at monofluorinated sp3 -hybridized carbons via C-F bond cleavage, including cross-coupling and multi-component coupling reactions. The C-F bond cleavage mechanisms on the sp3 -hybridized carbon centers can be primarily categorized into three types: Lewis acids promoted F atom elimination to generate carbocation intermediates; nucleophilic substitution with metal or carbon nucleophiles supported by the activation of C-F bonds by coordination of Lewis acids; and the cleavage of C-F bonds via a single electron transfer. The characteristic features of alkyl fluorides, in comparison with other (pseudo)halides as promising electrophilic coupling counterparts, are also discussed.

Mechanochemistry as a green method in organic chemistry and its applications

Abstract Activation of chemical reactions in the solid state by mechanical energy represents a novel method with a high potential to be used in organic chemistry and various applications. There are several advantages over the classical reactions which are carried out in solution. Green aspects are in the avoidance of organic solvents, which diminishes environmental impact, whereas shortening of reaction times and room temperature conditions reduce the energy input. Furthermore, mechanochemical reactions could lead to products which cannot be obtained by solution chemistry or are produced by higher atom efficiency. The realization of the simplicity of the method and its advantages by chemists has led to increased application. The basics of the method and selected reactions are illustrated, in order to introduce this environmentally friendly method and to widen its use by the organic science community.

Synthesis, Biological and In Silico Studies of Griseofulvin and Usnic Acid Sulfonamide Derivatives as Fungal, Bacterial and Human Carbonic Anhydrase Inhibitors.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of griseofulvin and usnic acid sulfonamides were synthesized and tested as possible CA inhibitors. Since β- and γ- classes are expressed in microorganisms in addition to the α- class, showing substantial structural differences to the human isoforms they are also interesting as new antiinfective targets with a different mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Griseofulvin and usnic acid sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX as well as β- and γ-CAs from different bacterial and fungal strains, was evaluated by a stopped-flow CO2 hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the three γ-CAs and Malassezia globosa (MgCA) enzyme. Six compounds (1b-1d, 1h, 1i and 1j) were more potent than AAZ against hCA I while five (1d, 1h, 1i, 1j and 4a) showed better activity than AAZ against the hCA II isoform. Moreover, all compounds appeared to be very potent against MgCA with a Ki lower than that of the reference drug. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of human CAs.

Drimane Sesquiterpene Alcohols with Activity against Candida Yeast Obtained by Biotransformation with Cladosporium antarcticum.

Fungal biotransformation is an attractive synthetic strategy to produce highly specific compounds with chemical functionality in regions of the carbon skeleton that are not easily activated by conventional organic chemistry methods. In this work, Cladosporium antarcticum isolated from sediments of Glacier Collins in Antarctica was used to obtain novel drimane sesquiterpenoids alcohols with activity against Candida yeast from drimendiol and epidrimendiol. These compounds were produced by the high-yield reduction of polygodial and isotadeonal with NaBH4 in methanol. Cladosporium antarcticum produced two major products from drimendiol, identified as 9α-hydroxydrimendiol (1, 41.4 mg, 19.4% yield) and 3β-hydroxydrimendiol (2, 74.8 mg, 35% yield), whereas the biotransformation of epidrimendiol yielded only one product, 9β-hydroxyepidrimendiol (3, 86.6 mg, 41.6% yield). The products were purified by column chromatography and their structure elucidated by NMR and MS. The antifungal activity of compounds 1-3 was analyzed against Candida albicans, C. krusei and C. parapsilosis, showing that compound 2 has a MIC lower than 15 µg/mL against the three-pathogenic yeast. In silico studies suggest that a possible mechanism of action for the novel compounds is the inhibition of the enzyme lanosterol 14α-demethylase, affecting the ergosterol synthesis.

Condensation Reactions of Aromatic Aldehydes with Active Methylene Compounds: The Beneficial Sinergy of Alkaline Ionic Liquid in One Pot Synthesis

Background: In recent times, there has been on-going interest in developing convenient and environmentally friendly synthetic methods in organic chemistry. The use of ionic liquid catalysts in organic synthesis is a developing area that allows reactions to be run at low temperatures and without solvents. Literature overview revealed that room temperature supported ionic liquid catalysis is a developing field in catalytic science with huge application in organic synthesis. Hence in this current article, our focus is on the one-pot synthesis of arylidene derivatives with the use of ([bmim] OH) ionic liquid. Objectives: We describe here the use of an ionic liquid catalyst, 1-n-butyl-3-methylimidazolium hydroxide, [bmim] OH), in the convenient one pot synthesis of arylidene derivatives by the reaction of the active methylene compound, malononitrile, with pyrazole aromatic aldehydes under microwave irradiation. Methods: The functionalized ionic liquid, 1-n-butyl-3-methylimidazolium hydroxide ([bmim] OH), catalyzed Knoevenagel condensation reactions of pyrazole aromatic aldehydes with active methylene compound malononitrile carried out under microwave irradiation. The reaction progress was monitored by thin layer chromatography and the synthesized compounds were further characterized by NMR spectroscopy. Results: This proposed work demonstrates the utility of the use of the ionic liquid catalyst [bmim] OH, in the suitable, high yield (80-95%) microwave assisted reactions of pyrazole aromatic aldehydes with the active methylene compound, malononitrile. Conclusion: An eco-friendly synthesis of pyrazole derivatives has been demonstrated using ([bmim] OH) ionic liquid as a catalyst for the Knoevenagel condensation reactions of pyrazole aromatic aldehydes and malononitrile with microwave irradiation. The advantages of this green method are its convenience, mild reaction conditions, and high product yields (80-95%).

Design, Synthesis, and Biological Activity of a Novel Series of 2-Ureidonicotinamide Derivatives Against Influenza A Virus.

Viral resistance to existing inhibitors and the time-dependent effectiveness of neuraminidase inhibitors have limited the number of antivirals that can be used for prophylaxis and therapeutic treatment of severe influenza infection. Thus, there is an urgent need to develop new drugs to prevent and treat influenza infection. The aims of this study was to design and synthesize a novel series of 2-ureidonicotinamide derivatives and evaluate their anti-IAV activities. Furthermore, we predicted the abilities of these compounds to inhibit the PA-PB1 subunit and forecasted the docking poses of these compounds with RNA polymerase protein (PDB ID 3CM8). The novel designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their abilities inhibiting RNP and against influenza A virus. In addition, the 23 synthesized molecules were subjected to the generated pharmacophore Hypo1 to forecast the activity target PA-PB1 subunit of RNA polymerase. The ADMET pharmacokinetic parameters were calculated by the ADMET modules in Discovery Studio 2016. The docking results helped us demonstrate the possible interactions between these compounds with 3CM8. The synthesized 2-ureidonicotinamide derivatives were characterized as potent anti-influenza inhibitors. The target compounds 7b and 7c demonstrated significant antiviral activities and could be considered as novel lead compounds of antiviral inhibitors. In addition, compound 7b revealed suitable ADME properties expressed and might be a significant RNA polymerase inhibitor targeting the PA-PB1 subunit based on the predictable results and the docking results. This study revealed a novel series of compounds that might be useful in the search for an effective drug against the influenza virus.

Palladium-Catalyzed Tandem Ester Dance/Decarbonylative Coupling Reactions.

"Dance reaction" on the aromatic ring is a powerful method in organic chemistry to translocate functional groups on arene scaffolds. Notably, dance reactions of halides and pseudohalides offer a unique platform for the divergent synthesis of substituted (hetero)aromatic compounds when combined with transition-metal-catalyzed coupling reactions. Herein, we report a tandem reaction of ester dance and decarbonylative coupling enabled by palladium catalysis. In this reaction, 1,2-translocation of the ester moiety on the aromatic ring is followed by decarbonylative coupling with nucleophiles to enable the installation of a variety of nucleophiles at the position adjacent to the ester in the starting material.

Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. On the other hand, in microorganisms, the β- and γ- classes are expressed in addition to the α- class, showing substantial structural differences to the human isoforms. In this scenario, not only human but also bacterial CAs are of particular interest as new antibacterial agents with an alternative mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Pyrazolo[4,3-c]pyridine sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX and XII, and β- and γ-CAs from three different bacterial strains, was evaluated by a stopped-flow CO2 hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the 3β- and 3γ-CAs. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX. Four compounds (1f, 1g, 1h and 1k) were more potent than AAZ against hCA I. Furthermore, compound 1f also showed better activity than AAZ against the hCA II isoform. Moreover, ten compounds out of eleven appeared to be very potent against the γ-CA from E.coli, with a Ki much lower than that of the reference drug. Most of the compounds showed better activity than AAZ against hCA I as well as the γ-CA from E.coli and the β-CA from Burkholderia pseudomallei (BpsCAβ). Compounds 1f and 1k showed a good selectivity index against hCA I and hCA XII, while 1b was selective against all 3β-CA isoforms from E.coli, BpsCA, and VhCA and all 3γ-CA isoforms from E.coli, BpsCA and PgiCA.

Synthesis, Biological Evaluation and Molecular Docking Studies of 5-Indolylmethylen-4-oxo-2-thioxothiazolidine Derivatives.

Background: Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using the classical organic chemistry methods. Prediction of biological activity spectra was carried out using PASS and PASS-based web applications. Pharmacophore modeling in LigandScout software was used for quantitative modeling of the antibacterial activity. Antimicrobial activity was evaluated using the microdilution method. AutoDock 4.2® software was used to elucidate probable bacterial and fungal molecular targets of the studied compounds. Results: All compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Three compounds were tested against resistant strains MRSA, P. aeruginosa and E. coli and were found to be more potent than MRSA than reference drugs. All compounds demonstrated a higher degree of antifungal activity than the reference drugs bifonazole (6–17-fold) and ketoconazole (13–52-fold). Three of the most active compounds could be considered for further development of the new, more potent antimicrobial agents. Conclusion: Compounds 5b (Z)-3-(3-hydroxyphenyl)-5-((1-methyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one and 5g (Z)-3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid as well as 5h (Z)-3-(5-((5-methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid can be considered as lead compounds for further development of more potent and safe antibacterial and antifungal agents.