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Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated for anticancer activity and ability to inhibit tubulin polymerization in vitro. Notably, pyrrolo[1,2-a]quinoline 10a was active on most tested cell lines, performing better than control phenstatin in several cases, most notably on renal cancer cell line A498 (GI50 27 nM), while inhibiting tubulin polymerization in vitro. In addition, this compound was predicted to have a promising ADMET profile. The molecular details of the interaction between compound 10a and tubulin were investigated through in silico docking experiments, followed by molecular dynamics simulations and configurational entropy calculations. Of note, we found that some of the initially predicted interactions from docking experiments were not stable during molecular dynamics simulations, but that configurational entropy loss was similar in all three cases. Our results suggest that for compound 10a, docking experiments alone are not sufficient for the adequate description of interaction details in terms of target binding, which makes subsequent scaffold optimization more difficult and ultimately hinders drug design. Taken together, these results could help shape novel potent antiproliferative compounds with pyrrolo-fused heterocyclic cores, especially from an in silico methodological perspective.

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This study presents the synthesis, structural characterization, and in vitro evaluation of anticancer activity of some newly benzo[f]quinoline derivatives. The synthesis is facile and efficient, involving two steps: quaternization of nitrogen heterocycle followed by a [3+2] dipolar cycloaddition reaction. The synthesized compounds were characterized by FTIR, NMR, and X-ray diffraction on monocrystal in the case of compounds 6c and 7c. An in vitro single-dose anticancer assay of eighteen benzo[f]quinoline compounds, quaternary salts, and cycloadducts, was performed. The results showed that the most active compounds were quaternary salts 3d and 3f with aromatic R substituents. Quaternary salt 3d revealed non-selective activity against all types of cancer cells, while salt 3f exhibited a highly selective activity against leukemia cells. Compound 3d also presented remarkable cytotoxic efficiency against four distinct types of cancer cells-namely, non-small cell lung cancer HOP-92, melanoma LOX IMVI, melanoma SK-MEL-5, and breast cancer MDA-MB-468. Compound 3f was selected for five-dose screening. The study also includes SAR correlations.

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This paper describes the synthesis and characterization of new organic semiconductors based on pyrrolo[1,2-i][1,7]phenanthrolines in the form of thin layers. The thin layers, produced via the spin coating method (with a thickness of 10-11 µm), were investigated for their electrical and optical properties. After heat treatment at temperatures ranging from 210 to 240 °C, the layers displayed consistent and reproducible properties. The layers exhibited n-type semiconductor behavior, with a thermal activation energy (Ea) in the range of 0.75-0.78 eV. Additionally, the layers showed transmittance values of 84-92% in the visible and near-infrared spectral ranges, with a direct optical band gap (Egod) ranging from 3.13 to 4.11 eV. These thin layers have potential applications in electronic devices such as thermistors, as well as in nanoelectronics and optoelectronics. Overall, these new organic semiconductors show promising properties for practical implementation in various electronic applications.

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This work reports a study on structural, electrical and optical properties of some recently synthesized pyrrolo[1,2-i][1,7] phenanthrolines derivatives in thin films. The thin films were deposited onto glass substrates by spin coating technique, using chloroform as solvent. The obtained films exhibited a polycrystalline structure with an n-type semiconductor behavior after heat treatment in the temperature range 293-543 K, specific to each sample. The thermal activation energy lies between 0.68 and 0.78 eV, while the direct optical band gap values were found in the range 4.17-4.24 eV. The electrical and optical properties of the investigated organic semiconductor films were discussed in relation to microstructural properties, determined by the molecular structure. The investigated organic compounds are promising for applications in organic optoelectronics and nanoelectronics.

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Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compound 9a showed a broad spectrum of antiproliferative activity against cancer cell lines representing leukemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast and prostate cancer. In vitro assays and molecular docking revealed tubulin interaction properties of compound 9a.

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Fifteen new 1,10-phenanthrolines disubstituted at positions 2 and 9 via amide bonds with different heterocycles have been designed and synthesized as G-quadruplex DNA stabilizers. Ten compounds were evaluated for the in vitro anticancer activity against 60 human tumor cell lines panel, four of them showing a very good inhibitory activity on several cell lines. To assess the ability of the most active compounds to interact with G-quadruplex DNA (G4-DNA), circular dichroism experiments were performed. The potency of the compounds to stabilize the G4-DNA has been shown from the thermal denaturation experiments. The mechanism of compounds binding to DNA and to G4-DNA was theoretically investigated by molecular docking studies. The experimental results demonstrated excellent capacity of the two compounds bearing two pyridin-3-yl residues (methylated and non-methylated) to act as selective G-quadruplex binders with promising anticancer activity.

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We present herein a straightforward and efficient pathway for the synthesis of pyrrolophthalazine cycloadducts via Huisgen [3 + 2] dipolar cycloaddition reactions of phthalazinium ylides to methyl propiolate or dimethyl acetylenedicarboxylate (DMAD). A thoroughly comparative study concerning the efficiency of synthesis, conventional thermal heating (TH) versus microwave (MW) and ultrasound (US) irradiation, has been performed. The cycloaddition reactions of phthalazinium ylides to methyl propiolate occur regiospecific, with a single regioisomer being obtained. Under conventional TH, the cycloaddition reaction of phthalazinium ylides with DMAD occurs to a mixture of inseparable partial and fully aromatized pyrrolophthalazine cycloadducts, while MW or US irradiation are leading only to fully aromatized compounds, with the reactions becoming selective. A feasible mechanism for formation of fully aromatized compounds is presented. Besides selectivity, it has to be noticed that the reaction setup under MW or US irradiation offer a number of other certain advantages: higher yields, decreasing of the amount of used solvent comparative with TH, decreasing of the reaction time from hours to minutes and decreasing of the consumed energy; consequently, these reactions could be considered environmentally friendly.

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We have designed and synthesized a series of novel, supramolecular, long-lived fluorescent probes based on the host-guest inclusion complexes formation between fluorescent indolizinyl-pyridinium salts and ß-cyclodextrin. Fluorescence and electrospray ionisation mass spectrometry experiments, supported by theoretical molecular docking studies, were utilized in the monitoring of the inclusion complexes formation, evidencing the appearance of corresponding 1:1 and 1:2 species. Additionally, the influence of the guest molecule over the aggregation processes of the cyclodextrin inclusion complexes was investigated by transmission electron microscopy. The absence of cytotoxicity, cellular permeability, long-lived intracellular fluorescence, and in time specific accumulation within acidic organelles identified the investigated supramolecular entities as remarkable candidates for intracellular fluorescence probes. Co-staining experiments using specific organelle markers revealed the fact that, after a 24-h incubation period, the inclusion complexes accumulate predominantly in lysosomes rather than in mitochondria. This study opens new possibilities for a broad range of fluorescent dyes with solubility and high toxicity issues, able to form inclusion complexes with ß-cyclodextrin, to be tested as intracellular fluorescence probes.

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A potential microtubule destabilising series of new indolizine derivatives was synthesised and tested for their anticancer activity against a panel of 60 human cancer cell lines. Compounds 11a, 11b, 15a, and 15j showed a broad spectrum of growth inhibitory activity against cancer cell lines representing leukaemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast, and prostate. Among them, compound 11a was distinguishable by its excellent cytostatic activity, showing GI50 values in the range of 10-100 nM on 43 cell lines. The less potent compounds 15a and 15j in terms of GI50 values showed a high cytotoxic effect against tested colon cancer, CNS cancer, renal cancer and melanoma cell lines and only on few cell lines from other types of cancer. In vitro assaying revealed tubulin polymerisation inhibition by all active compounds. Molecular docking showed good complementarity of active compounds with the colchicine binding site of tubulin.

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Microwave (MW) assisted reactions have became a powerful tool in azaheterocycles chemistry during the last decades. Five and six membered ring azaheterocycles are privileged scaffolds in modern medicinal chemistry possessing a large variety of biological activity. This review is focused on the recent relevant advances in the MW assisted reactions applied to azaheterocyclic derivatives and their medicinal chemistry applications from the last five years. The review is divided according to the main series of azaheterocycles, more precisely 5- and 6-membered ring azaheterocycles (with one, two, and more heteroatoms) and their fused analogues. In each case, the reaction pathways, the advantages of using MW, and considerations concerning biological activity of the obtained products were briefly presented.

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Three series of fused pyrrolophenanthroline derivatives were designed as analogues of phenstatin and synthesized in two steps starting with 1,7-phenanthroline, 4,7-phenanthroline and 1,10-phenanthroline, respectively. Two (Compounds 8a and 11c) of the four compounds tested against a panel of sixty human cancer cell lines of the National Cancer Institute (NCI) exhibited significant growth inhibition activity on several cell lines. Compound 11c showed a broad spectrum in terms of antiproliferative efficacy with GI50 values in the range of 0.296 to 250 µM. Molecular docking studies indicated that Compounds 8a and 11c are accommodated in the colchicine binding site of tubulin in two different ways.

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Two new series of heterocyclic derivatives with potential anticancer activity, in which a pyrrolo[1,2-b]pyridazine or a pyrrolo[2,1-a]phthalazine moiety was introduced in place of the 3'-hydroxy-4'-methoxyphenyl ring of phenstatin have been synthesised and their structure-activity relationship (SAR) was studied. Fourteen of the new compounds were evaluated for their in vitro cytotoxic activity by National Cancer Institute (NCI) against 60 human tumour cell lines panel. The best five compounds in terms of in vitro growth inhibition were screened in the second stage five dose-response studies, three of them showing a very good antiproliferative activity with GI50<100 nM on several cell lines including colon, ovarian, renal, prostate, brain and breast cancer, melanoma and leukemia. Docking experiments on the biologically active compounds showed a good compatibility with the colchicine binding site of tubulin.

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A series of 13 compounds having a monoindolizine mono-salt skeleton was designed and synthesised in order to evaluate their antimycobacterial activity. The synthesis is efficient, involving only three steps: two alkylations and one 3 + 2 dipolar cycloaddition. The antimicrobial activity against Mycobacterium tuberculosis H37Rv grown under aerobic conditions was evaluated, eight compounds showing a very good antimycobacterial activity. SAR correlation reveals a certain influence of the R substituent from the para position of benzoyl moiety at position 3 of indolizine. The most active five compounds passed the second stage of anti-TB testing, the assay demonstrating that they are potent against both replicating and non-replicating Mtb, have a bactericidal mechanism of action, are active against drug-resistant Mtb strains, present a moderate to good activity against nontuberculous mycobacteria, a good intracellular activity, and a moderate to high cytotoxicity. For one compound showing a promising anti-TB profile, a complete ADMET study has been performed.

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A study concerning design, synthesis, structure and in vitro antimycobacterial and anticancer evaluation of new fused derivatives with pyrrolo[2,1-c][4,7]phenanthroline skeleton is described. The strategy adopted for synthesis involves a [3 + 2] dipolar cycloaddition of several in situ generated 4,7-phenanthrolin-4-ium ylides to different substituted alkynes and alkenes. Stereo- and regiochemistry of cycloaddition reactions were discussed. The structure of the new compounds was proven unambiguously, single-crystal X-ray diffraction studies including. The antimycobacterial and anticancer activity of a selection of new synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv under aerobic conditions and 60 human tumour cell line panel, respectively. Five of the tested compounds possess a moderate antimycobacterial activity, while two of the compounds have a significant antitumor activity against renal cancer and breast cancer.

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We report herein a feasible study concerning the design, synthesis, structure and in vitro antimycobacterial and anticancer activity of two new classes (containing four and five fused rings) of indolizine with phenanthroline skeleton. The preparation is straight and efficient, involving a Huisgen [3+2] dipolar cycloaddition of cycloimmonium ylides to alkynes or alkenes dipolarophiles. The cycloaddition reactions are highly stereo- or regioselective, according with the dipolarophiles nature. The structure of the new compounds was assigned unambiguously, X-ray analysis including. The primary antimycobacterial screening reveals that one of the thirteen tested compounds had a good activity against Mycobacterium tuberculosis H37Rv under aerobic conditions. The antiproliferative evaluation against a NCI 60 human tumor cell line panel, revealed that two indolizine with phenanthroline skeleton exhibit a selective and significant antitumor growth inhibitory activity against Breast Cancer (MCF7 and T-47D) and a slightly moderate activity against some forms of Leukemia, Non-Small Cell Lung Cancer, Renal Cancer and Breast Cancer (MDA-MB-468). The X-ray diffraction study of the indolizines with phenanthroline skeleton prove a flat coplanar structure which, corroborated with their anticancer activity, allow us to suggest that an interaction with DNA (via an intercalation mechanism) would be reasonable.

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Palladium(II) complexes with Schiff bases ligands derived from salicylaldehyde and amino acids (Ala, Gly, Met, Ser, Val) have been synthesized and characterized by Fourier transform (FT)-IR, UV-Vis and (1)H-NMR spectroscopy. The electrospray mass spectrometry (ES-MS) spectrometry confirms the formation of palladium(II) complexes in 1/2 (M/L) molar ratio. All the Pd(II) complexes 1, [Pd(SalAla)2]Cl2; 2, [Pd(SalGly)2]Cl2; 3, [Pd(SalMet)2]Cl2; 4, [Pd(SalSer)2]Cl2; 5, [Pd(SalVal)2]Cl2; have shown antibacterial activity against Gram-positive bacteria Staphylococcus aureus and Gram-negative bacteria Escherichia coli.

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Three classes of fused bipyridine heterocycles were designed, synthesized and evaluated for their antimycobacterial activities. The method for preparation of fused bipyridine derivatives is straight and efficient. The primary antimycobacterial screening reveals that mono-indolizine mono-salts are displaying potency superior to the second-line antitubercular drugs Cycloserine and Pyrimethamine and, equal as the first line anti-TB Ethambutol. The data from Cycle-2 screening assay (MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation) confirm the promising anti-TB results from Cycle-1 for mono-indolizine mono-salts. These data indicate that mono-indolizine mono-salt 6d is a potent compound against both replicating and non-replicating Mycobacterium tuberculosis, is active against both extracellular and intracellular organisms, has a bacteriostatic mechanism of action and has basically no toxicity. We see no influence concerning the anti-TB activity of the fused-pyridine substituents.

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A series of D-glucose derivatives that have been modified at C-4 were synthesised from D-galactose as potential chain terminators of cellulose biosynthesis. Two compounds displayed herbicidal activity in pre-emergence tests and in addition a cell expansion assay at higher concentrations revealed symptomology of a third compound that was indicative of inhibition of cellulose biosynthesis.

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A series of UDP-D-glucose derivatives and precursors that have been modified at C-3 were synthesised from D-glucose as potential chain terminators of beta-glucan biosynthesis. None of the UDP-derivatives or the precursors tested displayed significant anti-fungal activity in a series of germination assays on the dermatophyte Trichophyton rubrum.

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