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This work designed and exploited a series of unique naphthalimide triazoles as antifungal molecules starting from naphthalic anhydride. The structures of the target compounds were confirmed by spectra. The antifungal activities showed that these naphthalimide triazoles against A. fumigatus exhibited superior bioactivities to fluconazole, especially the highly active compound 5j showed low toxicity to normal cells, no obvious drug resistance and rapid fungicidal potentiality. Further studies revealed that 5j could not only block the replication of microbial DNA by embedding in DNA to form supramolecular complexes, but also damage the cell membrane and induce ROS generation to affect the survival of fungi. Moreover, 5j could form a biosupramolecule with sterol 14-α demethylase (CYP51B) of A. fumigatus by four hydrogen bonds, and thus affect enzyme function to achieve anti- A. fumigatus purpose. These results revealed that these compounds exhibited multifarious antifungal effect. Therefore, this work implied that naphthalimide triazoles with this novel structural framework could be the potential anti- A. fumigatus drugs.

This work did a new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antimicrobial agents. A class of novel hybrids of quinolone, aminothiazole, piperazine and oxime fragments were designed for the first time, conveniently synthesized as well as characterized by 1H NMR, 13C NMR and HRMS spectra. Biological activity showed that some of the synthesized compounds exhibited good antimicrobial activities in comparison with the reference drugs. Especially, O-methyl oxime derivative 10b displayed excellent inhibitory efficacy against MRSA and S. aureus 25923 with MIC values of 0.009 and 0.017 mM, respectively. Further studies indicated that the highly active compound 10b showed low toxicity toward BEAS-2B and A549 cell lines and no obvious propensity to trigger the development of bacterial resistance. Quantum chemical studies have also been conducted and rationally explained the structural features essential for activity. The preliminarily mechanism exploration revealed that compound 10b could not only exert efficient membrane permeability by interfering with the integrity of cells, bind with topoisomerase IV–DNA complex through hydrogen bonds and π-π stacking, but also form a steady biosupramolecular complex by intercalating into DNA to exert the efficient antibacterial activity. The supramolecular interaction between compound 10b and human serum albumin (HSA) was a static quenching, and the binding process was spontaneous, where hydrogen bonds and van der Waals force played vital roles in the supramolecular transportation of the active compound 10b by HSA.

A series of aminothiazolyl norfloxacin analogues as a new type of potential antimicrobial agents were synthesized and screened for their antimicrobial activities. Most of the prepared compounds exhibited excellent inhibitory efficiencies. Especially, norfloxacin analogue II-c displayed superior antimicrobial activities against K. pneumoniae and C. albicans with MIC values of 0.005 and 0.010 mM to reference drugs, respectively. This compound not only showed broad antimicrobial spectrum, rapid bactericidal efficacy and strong enzymes inhibitory potency including DNA gyrase and chitin synthase (CHS), low toxicity against mammalian cells and no obvious propensity to trigger the development of bacterial resistance, but also exerted efficient membrane permeability, and could effectively intercalate into K. pneumoniae DNA to form a steady supramolecular complex, which might block DNA replication to exhibit their powerful antimicrobial activity. Quantum chemical studies were also performed to explain the high antimicrobial activities. Molecular docking showed that compound II-c could bind with gyrase–DNA and topoisomerase IV–DNA through hydrogen bonds and π-π stacking.

Novel sulfonamide-based four-component molecular hybrids as potential DNA-targeting antimicrobial agents were developed from marketed acetanilide through convenient procedures. Biological assays indicated that a few of the target compounds showed significant inhibitory efficiencies toward the tested bacteria and fungi. Noticeably, metronidazole hybrid 6a exhibited a lower minimum inhibitory concentration (MIC) value of 0.019 mM against clinical drug-resistant Escherichia coli ( E. coli), which showed to be 84-fold more active than clinical norfloxacin and had no obvious toxicity toward human breast cancer MCF-7 cells. Synergistic combinations of compound 6a with clinical antibacterial or antifungal drugs could improve the antimicrobial efficiency. Further molecular modeling indicated that the active molecule 6a could bind with THR-199, HIS-64, and GLN-92 residues of human carbonic anhydrase isozyme II through hydrogen bonds and was also able to insert into base-pairs of the DNA hexamer duplex by forming hydrogen bonds. The preliminary exploration of the antibacterial mechanism suggested that compound 6a was capable of disturbing the E. coli membrane effectively and intercalating into clinical resistant E. coli bacterial DNA through noncovalent bonds to form a supramolecular complex, thus exerting its powerful antimicrobial activity. This might suggest a great possibility for hybrid 6a to be a DNA-targeting membrane active potentiator against clinical drug-resistant E. coli.

A series of berberine-derived thiazolidinediones as novel potential artificial DNA intercalators were developed via five steps from natural berberine. The biological evaluation showed that some of the target molecules exhibited good inhibitory potencies against the tested bacteria and fungi. Noticeably, compound 6b displayed excellent antibacterial activity with a quite low MIC value of 0.008 μmol mL−1 against MRSA. This compound not only showed low toxicity to hepatocyte LO2 cells and slow development of bacterial resistance, but also displayed efficient membrane penetrability. The DNA binding efficacy was investigated using molecular modeling and UV-vis absorption experiments. The docking study pointed out the specific binding sites and non-covalent interactions of butyl derivative 6b with MRSA DNA isomerase. The active molecule 6b could block DNA replication by intercalating into MRSA DNA to form a supramolecular complex and thus suppress the growth of MRSA strain. Quantum chemical studies were also performed to understand the relationship between biological activity and molecular structure. It was found that the highly active compound 6b could be supramolecularly transported by human serum albumin through hydrophobic interactions and hydrogen bonds. Furthermore, the drug combination of compound 6b with norfloxacin and fluconazole could enhance the antimicrobial efficacy.

As serious global drug resistance motivated the exploration of new structural drugs, we developed a type of novel structural aloe-emodin azoles as potential antibacterial agents in this work. Some target aloe-emodin azoles displayed effective activity against the tested strains, especially tetrazolyl aloe-emodin 4b showed a low MIC value of 2 μg mL(−1) towards MRSA, being more efficient than the reference drug norfloxacin (MIC = 8 μg mL(−1)). Also, the active molecule 4b exhibited low cytotoxicity against LO(2) cells with no distinct tendency to induce the concerned resistance towards MRSA. The tetrazolyl derivative 4b was preliminarily investigated for the possible mechanism; it was revealed that tetrazolyl derivative 4b could both disrupt the integrity of MRSA membrane and form 4b–DNA supramolecular complex by intercalating into DNA. Moreover, tetrazolyl aloe-emodin 4b could bind with MRSA DNA isomerase at multiple sites through hydrogen bonds in molecular simulation.

Two organic compounds, namely, 7a-(2-chlorophenyl)-7a,8a,9,10,11,12a-hexadronaptho-[1',2':4,5]furo[3,2-d]pyrrolo[2,1-b]oxazole (I) and 2-(4-fluorophenyl)-2-hydroxynaptho[2,1-b]furan- 1(2H)-one (II), were synthesised via microwave reaction using commercially available glyoxal monohydrate, β-Naphthol, pyrrolidine, and Cu(OAc)2 · H2O, and their crystal structures were determined by X-ray diffraction technique. The crystals of compound I are orthorhombic, sp. gr. P212121, a = 6.8750(5) A, b = 8.2248(9) A, c = 31.720(3) A, and Z = 4, while the crystals of compound II are monoclinic, sp. gr. P21/c, a = 7.4038(9) A, b = 18.592(2) A, c = 10.4589(12) A, β = 107.492(13)°, and Z = 4. The inter molecular O–H···O, C–H···O, and C–H···F hydrogen interactions play significant role in stabilizing the crystal structure in the compound II. In addition, aromatic π–π interactions are also observed in the structure of the compound II.

A series of novel unique structural organophosphorus aminopyrimidines were developed as potential DNA-targeting membrane active inhibitors through an efficient one-pot procedure from aldehydes, phosphonate and aminopyrimidine. The biological assay revealed that some of the prepared compounds displayed antibacterial activities. In particular, imidazole derivative 2c exhibited more potent inhibitory activity against MRSA with an MIC value of 4 μg mL-1 in comparison with the clinical drugs chloromycin and norfloxacin. Experiments revealed that the active molecule 2c had the ability to rapidly kill the tested strains without obviously triggering the development of bacterial resistance, showed low toxicity to L929 cells and could disturb the cell membrane. The molecular docking study discovered that compound 2c could bind with DNA gyrase via hydrogen bonds and other weak interactions. Further exploration disclosed that the active molecule 2c could also effectively intercalate into MRSA DNA and form a steady 2c-DNA supramolecular complex, which might further block DNA replication to exert powerful antibacterial effects.

Department of Chemistry, Uka Tarsadia University, Bardoli, Surat-394 350, Gujarat, India E-mail: satyamssd@gmail.com Medicinal Chemistry Department, Indian Institute of Integrative Medicine, Canal Road, Jammu-180 001, Jammu & Kashmir, India Bioorganic and Med. Chemistry Lab, School of Chemistry and Chemical Engineering, Southwest University, Chongqing-400715, China Manuscript received online 16 September 2019, revised 17 september 2019, accepted 18 September 2019 The utility of oxone has been extended to an efficient aromatizing agent and successfully applied to the aromatization of tetrahydro-β-carbolines under mild conditions, to produce aromatized β-carboline esters and amides. It is expediently applicable to all kinds of C-1 subsisted (aryl, alkyl, and acyl) tetrahydro-β-carboline esters. It also gives a direct and productive one-pot conversion of tetrahydro-β-carbolines ester to aromatized β-carboline amide. Further, the application of this method finds an easier route to the synthesis of marinacarbolines A and C.

The biological resistance of methicillin-resistant staphylococcus aureus (MRSA) has pushed synthetic antibiotics to the forefront. To combat the resistance of MRSA, our new effort directed towards the development of novel structural candidates of enone-bridged indole nitroimidazole scaffolds, and wished to shed some light on the combination of some single pharmacophore with different biological activities. Bioassay revealed that the active compound 4b gave a satisfactory inhibition on MRSA (MIC = 1 μg/mL) and could effectively prevent the development of bacterial resistance. Mechanism exploration indicated that molecule 4b could not only intercalate into MRSA deoxyribonucleic acid (DNA), but also permeate MRSA membrane and bind with penicillin-binding protein 2a (PBP2a), then decreased the expression of three relevant genes in MRSA. Furthermore, it was able to be stored and carried by human serum albumin (HSA), and the participation of metal ions in 4b-HSA system was helpful to improve the supramolecular transport behavior. Hybrid 4b also exhibited low cytotoxicity towards normal lung epithelial cell line BEAS-2B.

A novel class of 7-thiazoxime quinolones was developed as potential antimicrobial agents for the sake of bypassing resistance of quinolones. Biological assays revealed that some constructed 7-thiazoxime quinolones possessed effective antibacterial efficiency. Methyl acetate oxime derivative 6l exhibited 32-fold more active than ciprofloxacin against MRSA, which also possessed rapidly bactericidal ability and low toxicity towards mammalian cells. The combination use of 7-thiazoxime quinolone 6l and ciprofloxacin was able to improve antibacterial potency and effectively alleviate bacterial resistance. The preliminarily mechanism exploration revealed that compound 6l could destroy the cell membrane and insert into MRSA DNA to bind with DNA gyrase, then decrease the expression of gyrB and femB genes. The above results strongly suggested that methyl acetate oxime derivative 6l held a promise for combating MRSA infection.

An air-assisted, functional-group-driven, mild, additive-free, three-component synthetic approach to different 2-oxo acetamidines from 2-oxo aldehydes, secondary amines, and anilines was successfully developed. Mechanistically, the transformation proceeds through a highly unstable system ((RCOCHNN2)-N-1) that rearranges at room temperature and undergoes air-assisted dehydrogenation to different 2-oxo acetamidines.

In an effort for the development of novel antimicrobial agents, ethylenic conjugated coumarin thiazolidinediones as potential multi-targeting new antimicrobial compounds were synthesized through convenient procedures from commercially available resorcinol and were evaluated for their antimicrobial potency. Bioactive evaluation revealed that some of the prepared compounds showed strong antimicrobial activities towards the tested microorganisms including clinically drug-resistant strains. Especially, propargyl derivative 12b exhibited effective anti-MRSA potency with MIC value of 0.006 μmol/mL, which was highly advantageous over clinical antibacterial drug norfloxacin. Compound 12b showed rapid killing effect, low toxicity against hepatocyte LO2 cell line, and no obvious drug resistance development against MRSA. Preliminary exploration of action mechanism manifested that molecule 12b acted upon MRSA through forming stable supramolecular complex with bacterial DNA which might impede DNA replication. Molecular docking showed that compound 12b could bind with DNA-gyrase through hydrogen bonds.

Given the attractive ability of iminium ions to functionalize molecules directly at ostensibly unreactive positions, the reactivity of iminium ions, in which an α CH2 group is replaced by CO was explored. Background studies on the ability of such iminium cations to promote reactions via an iminium-catalyzed or iminium-equivalent pathway are apparently unavailable. Previously, tandem cross-coupling reactions were reported, in which an iminium ion undergoes nucleophilic 1,2-addition to give a putative three-component intermediate that abstracts a proton in situ and undergoes self-deamination followed by unprecedented DMSO/aerobic oxidation to generate α-ketoamides. However, later it was observed that iminium ions can generate valuable α-ketoamides through simple aerobic oxidation. In all reactions, iminium ions were generated in situ by reaction of 2-oxoaldehydes with secondary amines.

An air-assisted, functional-group-driven, mild, additive-free, three-component synthetic approach to different 2-oxo acetamidines from 2-oxo aldehydes, secondary amines, and anilines was successfully developed. Mechanistically, the transformation proceeds through a highly unstable system ((RCOCHNN2)-N-1) that rearranges at room temperature and undergoes air-assisted dehydrogenation to different 2-oxo acetamidines.

The deformylation of indole and azaindole-3-carboxaldehydes was achieved in the presence of anthranilamide and a solid acid heterogeneous catalyst under reflux conditions in 25–90% yield. The reaction proceeds via quinazolinone intermediate, which undergoes acid catalyzed cleavage to form deformylated product.

A highly efficient, novel, microwave-assisted, metal-free, diastereoselective synthesis of tetrahydrofuro[3,2-d]oxazole is disclosed. The synthesis of napthoxazoles is achieved for the first time without the aid of an external catalyst. On the contrary, our reactions generated naphthofuranones when treated in the presence of metals in microwave/thermal conditions. The unusual behavior of our reactions has further been explored in the generation of furanones from tetrahydrofuro[3,2-d]oxazole through the use of metals.

Highly efficient catalyst free methods for the synthesis of α-hydroxy-β-oxophosphonates and α-oxoesters have been described. The existence of a 2-oxo group in α-oxoaldehydes is a key factor in promoting the reaction of the tervalent phosphite form towards 2-oxoaldehydes in the synthesis of α-hydroxy-β-oxophosphonates. The in situ activated α-C–H atom of α-hydroxy-β-oxophosphonates sustains aerobic intramolecular nucleophilic displacement in a curious way to produce α-oxoester.

The pyrrolidine-catalyzed aerobic cross-coupling of glyoxals (I) with phenols, naphthols, indoles, and pyrroles as nucleophiles leads to diones (III) [42 examples].

A highly efficient, novel, microwave-assisted, metal-free, diastereoselective synthesis of tetrahydrofuro[3,2-d]oxazole is disclosed. The synthesis of napthoxazoles is achieved for the first time without the aid of an external catalyst. On the contrary, our reactions generated naphthofuranones when treated in the presence of metals in microwave/thermal conditions. The unusual behavior of our reactions has further been explored in the generation of furanones from tetrahydrofuro[3,2-d]oxazole through the use of metals.

Numerous glyoxals are prepared in situ from acetone (IIj), acetophenone derivatives (IIa-i) as well as other variously substituted acetophenone derivatives and subsequently transformed with tryptophane (I) to carbolines.

An efficient one-pot multi-component synthesis of flavans using perchloric acid supported on silica as a recyclable heterogeneous catalyst has been described. This is the first report of direct one-step construction of a flavan skeleton from a phenolic precursor. The method involves a Knoevenagel-type condensation leading to in situ formation of transient O-quinone methide which further undergoes [4 + 2]-Diels–Alder cycloaddition with styrene to yield a flavan skeleton. The method provides easy access to a wide range of bio-active natural products viz. flavonoids, anthocyanins and catechins.

Marine natural products offer an abundant source of pharmacologically active agents with great diversity and complexity, and the potential to produce valuable therapeutic entities. Indole alkaloids is one of the important class of marine-derived secondary metabolites, with wide occurrence amongst variety of marine sources such as sponges, tunicates, algae, worms and microorganisms and have been extensively studied for their biological activities. Among this chemical family, a sponge-derived bis-indole alkaloid fascaplysin (1) exhibited broad range of bioactivities including antibacterial, antifungal, antiviral, anti-HIV-1-RTase, p56 tyrosine kinase inhibition, antimalarial, anti-angiogenic, antiproliferative activity against numerous cancer cell lines, specific inhibition of cyclin-dependent kinase-4 (IC(50) 350 nM) and action as a DNA intercalator. In the present review, the chemical diversity of natural as well as synthetic analogues of fascaplysin has been reviewed with a detailed account on synthetic reports and pharmacological studies. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer agents.

Novel reactions under Pictet–Spengler conditions between tryptophan methyl ester/tryptamine and 2-oxoaldehydes have been developed and successfully utilized for the total synthesis of Merinacarboline (A and B), Eudistomin Y1, Pityriacitrin B, Pityriacitrin, Fascaplysin and analogues.