Construction of Diversified Penta-Spiro-Heterocyclic and Fused-Heterocyclic Frameworks with Potent Antitumor Activity.

Multiple-spiro/fused-heterocyclic frameworks containing indazolone are structurally unique and represent a class of potentially dominant skeletons. In this work, we successfully fulfilled Rh(III)-catalyst mediated substrate- and pH- controlled strategies to construct four novel types of complicated penta-spiro/fused-heterocyclic frameworks via C-H activation/[4+1] and [4+2] annulation cascades. This method had mild reaction conditions, a broad scope of substrates, moderate to good yields, and valuable applications, which could realize for the first time the generation of the novel di-spiro-heterocyclic and multiple fused-heterocyclic products with unique structures. More importantly, novel spiro[cyclohexane-indazolo[1,2-a]indazole] scaffold constructed by this method exhibited potent antitumor activity against a variety of refractory solid tumors and hematological malignancies in vitro. Overall, our work provided new insights into the construction of complex and diverse multiple spiro/fused-heterocyclic systems and offered novel valuable lead compounds for the discovery of antitumor drugs.

Design, synthesis and antibacterial evaluation of novel oxazolidinone derivatives nitrogen-containing fused heterocyclic moiety.

A series of novel oxazolidinone derivatives with nitrogen-containing fused heterocyclic moiety were designed and synthesized in this article. Their antibacterial activities were measured against S. aureus, MRSA and MSSA by MIC assay. Most of them exhibited potent activity against Gram-positive pathogens comparable to Linezolid and Radezolid. Compound 3b, which exhibited significant antibacterial activity with MIC values ranging 0.5-1.0 µg/mL, might be a promising drug candidate for further investigation.

Regioselective C-H Functionalization of the Six-Membered Ring of the 6,5-Fused Heterocyclic Systems: An Overview.

The regioselective C-H functionalization of the five-membered ring of the 6,5-fused heterocyclic systems is nowadays well documented due to its high reactivity compared to the six-membered ring. So, developing new procedures of C-H functionalization of the six-membered ring "by thinking out of the box" is extremely challenging, which explains the limited number of reports published to date. This review paper aims to highlight advances achieved in this emerging chemistry research and discusses recently reported methods.

Design, synthesis, and biological evaluation of imidazopyridine-linked thiazolidinone as potential anticancer agents.

In this study, two series of imidazopyridine-linked thiazolidinone rings (5a-h and 6a-h) constituting 16 new compounds were synthesized and tested for their antiproliferative activity against a panel of three human cancer cell lines, that is, MCF-7 (human breast cancer), A549 (human lung cancer), and DU145 (human prostate cancer). Three compounds, 5h, 6f, and 6h, exhibited remarkable results against all three cell lines, but compound 6h was found to be the most active one against the breast cancer cell line. Among all the synthesized compounds, 6h displayed the highest antioxidant results. Furthermore, the potent compounds 5h, 6f, and 6h showed no signs of toxicity at doses ranging from 50 to 500 mg/kg of animal body weight. The biochemical parameters (SGOT and SGPT) of compound 6h nearly matched the control in hepatotoxicity studies. The molecular docking and MM-GBSADG binding studies are in agreement with the in vitro anticancer and antioxidant activity results. The most promising compound 6h was found to have the highest docking score and binding energy, and its absorption, distribution, metabolism, and excretion (ADME) parameters are in the acceptable range. Thus, it can be concluded that 6h, an imidazopyridine derivative endowed with a thiazolidinone ring system, has the potential to be developed as an anticancer agent.

5-Amino-pyrazoles: potent reagents in organic and medicinal synthesis.

5-Amino-pyrazoles have proven to be a class of fascinating and privileged organic tools for the construction of diverse heterocyclic or fused heterocyclic scaffolds. This review presents comprehensively the applications of 5-amino-pyrazoles as versatile synthetic building blocks in the synthesis of remarkable organic molecules with an emphasis on versatile functionalities. Following a brief introduction of synthesis methods, planning strategies to construct organic compounds, particularly diverse heterocyclic scaffolds, such as poly-substituted heterocyclic compounds and fused heterocyclic compounds via 5-amino-pyrazoles, have been summarized. Fused heterocycles are classified as bicyclic, tricyclic, tetracyclic, and spiro-fused pyrazole derivatives. These outstanding compounds synthesized via wide variety of approaches include conventional reactions, one-pot multi-component reactions, cyclocondensation, cascade/tandem protocols, and coupling reactions. 5-Amino-pyrazoles represent a class of promising functional reagents, similar to the biologically active compounds, highlighted with diverse applications especially in the field of pharmaceutics and medicinal chemistry. Notably, this critical review covers the articles published from 1981 to 2018.

Efficient synthesis of pyrazolopyridines containing a chromane backbone through domino reaction.

An efficient approach for the synthesis of pyrazolopyridines containing the aminochromane motif through a base-catalyzed cyclization reaction is reported. The synthesis was carried out through a three-component reaction of (arylhydrazono)methyl-4H-chromen-4-one, malononitrile, primary amines in the presence of Et3N at room temperature. However, carrying out the reaction under the same conditions without base led to a fused chromanyl-cyanopyridine. High selectivity, high atom economy, and good to high yields in addition to mild reaction conditions are the advantages of this approach.

Crystal structure of 3-[4-(pyrimidin-2-yl)piperazin-1-ium-1-yl]butano-ate.

The title compound, C12H18N4O2, crystallizes in the zwitterionic form with protonation at the N atom of the piperazine ring bearing the carboxylate group. The piperazine ring adopts a slightly distorted chair conformation. In the crystal, N-H⋯O hydrogen bonds are observed, forming chains along [010]. The packing is consolidated by C-H⋯O inter-actions, which generate a three-dimensional network.

13-Nitro-benzo[a][1,4]benzo-thia-zino[3,2-c]phenoxazine.

In the title compound, C22H11N3O3S, dihedral angle between the phenyl rings on the periphery of the molecule is 8.05 (18)°. In the crystal, aromatic π-π stacking distance and short C-H⋯O contacts are observed. The maximum absorption occurs at 688 nm.

Benzo[a][1,4]benzothia-zino[3,2-c]phenothia-zine.

The title compound, C22H12N2S2, crystallizes in space group P21/c with four mol-ecules in the asymmetric unit. The heterocyclic mol-ecule is quasi-planar with a dihedral angle between the phenyl rings on the periphery of the mol-ecule of 1.73 (19)°. Short H⋯S (2.92 Å) and C-H⋯π [2.836 (3) Å] contacts are observed in the crystal with shorted π-π stacking distances of 3.438 (3) Šalong the b axis. Surprisingly, and unlike a closely related material, this mol-ecule readily forms large crystals by sublimation and by slow evaporation from di-chloro-methane. The maximum absorbance in the UV-Vis spectrum is at 533 nm. Emission was measured upon excitation at 533 nm with a fluorescence λmax of 658 nm and cutoff of 900 nm.

Design and Synthesis of Novel Oxathiapiprolin Derivatives as Oxysterol Binding Protein Inhibitors and Their Application in Phytopathogenic Oomycetes.

Oomycetes, particularly those from the genus Phytophthora, are significant threats to global food security and natural ecosystems. Oxathiapiprolin (OXA) is an effective oomycete fungicide that targets an oxysterol binding protein (OSBP), while the binding mechanism of OXA is still unclear, which limits the pesticide design, induced by the low sequence identity of Phytophthora and template models. Herein, we generated the OSBP model of the well-reported Phytophthora capsici using AlphaFold 2 and studied the binding mechanism of OXA. Based on it, a series of OXA analogues were designed. Then, compound 2l, the most potent candidate, was successfully designed and synthesized, showing a control efficiency comparable to that of OXA. Moreover, field trial experiments showed that 2l exhibited nearly the same activity (72.4%) as OXA against cucumber downy mildew at 25 g/ha. The present work indicated that 2l could be used as a leading compound for the discovery of new OSBP fungicides.

A Comprehensive Review on Fused Heterocyclic as DNA Intercalators: Promising Anticancer Agents.

Since the discovery of DNA intercalating agents (by Lerman, 1961), a growing number of organic, inorganic, and metallic compounds have been developed to treat life-threatening microbial infections and cancers. Fused-heterocycles are amongst the most important group of compounds that have the ability to interact with DNA. DNA intercalators possess a planar aromatic ring structure that inserts itself between the base pairs of nucleic acids. Once inserted, the aromatic structure makes van der Waals interactions and hydrogen-bonding interactions with the base pairs. The DNA intercalator may also contain an ionizable group that can form ionic interactions with the negatively charged phosphate backbone. After the intercalation, other cellular processes could take place, leading ultimately to cell death. The heterocyclic nucleus present in the DNA intercalators can be considered as a pharmacophore that plays an instrumental role in dictating the affinity and selectivity exhibited by these compounds. In this work, we have carried out a revision of small organic molecules that bind to the DNA molecule via intercalation and cleaving and exert their antitumor activity. A general overview of the most recent results in this area, paying particular attention to compounds that are currently under clinical trials, is provided. Advancement in spectroscopic techniques studying DNA interaction can be examined in-depth, yielding important information on structure-activity relationships. In this comprehensive review, we have focused on the introduction to fused heterocyclic agents with DNA interacting features, from medicinal point of view. The structure-activity relationships points, cytotoxicity data, and binding data and future perspectives of medicinal compounds have been discussed in detail.

Discovery of fused heterocyclic carboxamide derivatives as novel α7-nAChR agonists: Synthesis, preliminary SAR and biological evaluation.

The α7 nicotinic acetylcholine receptor (α7 nAChR) has emerged as a promising therapeutic target for schizophrenia. In our previous work, a novel series of α7-nAChR agonists bearing scaffold of indolizine were discovered. To explore the effect of aromaticity on the activity and find more active agents, herein, fused heterocyclic carboxamide derivatives were designed and synthesized in this study. Based on the evaluation by two-electrode voltage clamp in Xenopus oocytes, 27 of the synthesized compounds showed obvious agonism of α7 nAChR. Particularly, compounds 10a and 10e showed significantly higher Emax than EVP-6124. The result illustrated the importance of aromaticity to the activity of agonism. Compound 10a, which showed EC50 of 1.88 µM and Emax of 72.4%, was further characterized comprehensively, including co-application with type II positive allosteric modulator PNU-120596, selectivity with other closely related ligand-gated ion channel, etc. The results showed that 10a showed moderate selectivity over other subtypes such as α4ß2 and α3ß4 nAChR. 10a evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. The analysis of binding mode and understanding of structure-activity relationship provided insights to develop more potent novel α7-nAChR agonists.

Performance Regulation of Thieno[3,2-b]benzothiophene π-Spacer-Based D-π-A Organic Dyes for Dye-Sensitized Solar Cell Applications: Insights From Computational Study.

Dye-sensitized solar cells (DSSCs) have been widely investigated; however, the development of promising dye sensitizers is still appealing. In this work, we perform a detailed theoretical search for high-efficiency D-π-A organic dyes using density functional theory and time-dependent density functional theory calculations. Specifically, we perform geometric optimization, and electronic structure and absorption spectra calculations for isolated dyes for two thieno[3,2-b]benzothiophene π-spacer-based D-π-A organic dyes SGT129 and SGT130, which show significant efficiency difference, before and after binding to a TiO2 semiconductor. The calculation results reveal that the coplanar configuration between the electron donor and the π-spacer can enhance electronic communication efficiently, thus facilitating intra-molecular charge transfer from the electron donor to the acceptor groups in SGT130. The absorption spectrum of SGT130 broadens and is red-shifted owing to the decreased bandgap. The higher light-harvesting efficiency, favorable intra-molecular charge transfer, larger shift of the conduction band edge in the TiO2 semiconductor, and slower charge recombination between the injected electrons in the TiO2 conduction band and the electrolyte explain the superior efficiency of SGT130 over that of SGT129. Using SGT130 as the reference dye, we further design four novel dyes 1-4 by modifying the π-spacer with electron-rich and electron-withdrawing moieties. Judging from the theoretical parameters influencing the short-circuit current and open-circuit voltage, we found that all dyes would perform better than SGT130 in terms of the favorable interfacial charge transfer (ICT) and light-harvesting efficiency, as well as the larger shift of the TiO2 conduction band edge. Our theoretical research is expected to provide valuable insights into the molecular modification of TBT-based D-π-A organic dyes for DSSC applications.

Fused Heterocyclic Compounds as Potent Indoleamine-2,3-dioxygenase 1 Inhibitors.

Uncontrolled metabolism of l-tryptophan (l-Trp) in the immune system has been recognized as a critical cellular process in immune tolerance. Indoleamine 2,3-dioxygenase 1 (IDO1) enzyme plays an important role in the metabolism of a local l-Trp through the kynurenine pathway in the immune systems. In this regard, IDO1 has emerged as a therapeutic target for the treatment of diseases that are associated with immune suppression like chronic infections, cancer, and others. In this study, we synthesized a series of pyridopyrimidine, pyrazolopyranopyrimidine, and dipyrazolopyran derivatives. Further lead optimizations directed to the identification of potent compounds, 4j and 4l (IC50 = 260 and 151 nM, respectively). These compounds also exhibited IDO1 inhibitory activities in the low nanomolar range in MDA-MB-231 cells with very low cytotoxicity. Stronger selectivity for the IDO1 enzyme (>300-fold) over tryptophan 2,3-dioxygenase (TDO) enzyme was also observed for these compounds. Hence, these fused heterocyclic compounds are attractive candidates for the advanced study of IDO1-dependent cellular function and immunotherapeutic applications.