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The synthesis of 1,8-naphthyridine derivatives fused with other heterocycles, such as chromenes and quinolines, as well as their behaviour as topoisomerase I inhibitors is studied. The preparation is carried out through a direct and simple process as an intramolecular [4 + 2] cycloaddition reaction between functionalized aldimines, obtained by the condensation of 2-aminopyridine and unsaturated aldehydes, and olefins. In particular, while no clear inhibitory activity is observed for chromeno[4,3-b][1,8]naphthyridine fused heterocycles, a very different result is observed for quinolino[4,3-b][1,8]naphthyridine derivatives. Experimental assays indicated that quinolino[4,3-b][1,8]naphthyridines inhibited the topoisomerase I enzymatic reaction behaving like a poison, as occurs with the natural TopI inhibitor, camptothecin. Furthermore, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV3), and on non-cancerous lung fibroblasts cell line (MRC5) was also screened., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Topoisomerases are important targets for therapeutic improvement in the treatment of some diseases, including cancer. Inhibitors and poisons of topoisomerase I can limit the activity of this enzyme in its enzymatic cycle. This fact implies an anticancer effect of these drugs, since most cancer cells are characterized by both a higher activity of topoisomerase I and a higher replication rate compared to non-cancerous cells. Clinically approved inhibitors include camptothecin (CPT) and its derivatives. However, their limitations have encouraged different research groups to prepare new compounds, proof of which are the numerous research works and patents, some of them in the last five years., Areas Covered: This review covers patent literature on topoisomerase I inhibitors and their application published between 2016-present., Expert Opinion: The highest contribution toward patent development has been obtained from academics or small biotechnology companies. The most important fields of innovation include the preparation of prodrugs or inhibitors combined with other agents, as biocompatible polymers or antibodies. A promising development of topoisomerase I inhibitors is expected in the next years, directed to the treatment of diverse diseases, specifically toward different types of cancer and infectious diseases, among others.

Heterocyclic nitrogen compounds, including fused 1,5-naphthyridines, have versatile applications in the fields of synthetic organic chemistry and play an important role in the field of medicinal chemistry, as many of them have a wide range of biological activities. In this review, a wide range of synthetic protocols for the construction of this scaffold are presented. For example, Friedländer, Skraup, Semmlere-Wolff, and hetero-Diels-Alder, among others, are well known classical synthetic protocols used for the construction of the main 1,5-naphthyridine scaffold. These syntheses are classified according to the nature of the cycle fused to the 1,5-naphthyridine ring: carbocycles, nitrogen heterocycles, oxygen heterocycles, and sulphur heterocycles. In addition, taking into account the aforementioned versatility of these heterocycles, their reactivity is presented as well as their use as a ligand for metal complexes formation. Finally, those fused 1,5-naphthyridines that present biological activity and optical applications, among others, are indicated.

This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, cross-coupling reactions, modification of side chains or formation of metal complexes. Finally, some properties and applications of these heterocycles studied during this period are examined.

This work describes the synthesis of the gold(i) complexes of phosphine sulphides. The formation of these new derivatives has been confirmed by X-ray crystallography. The coordination of gold(i) with the sulphur atom of the phosphine sulphides favors the inhibition of topoisomerase I as well as a high cytotoxicity of the gold(i)-complexed compounds against the cancer line A549 with IC 50 values in the nanomolar range and IC 50 values below 5 μM against the SKOV3 cell line. It should be noted that the cytotoxicities observed for the new gold(i) complexes are higher than those observed for phosphine sulphide ligands before binding to gold. Furthermore, the results also indicate that the presence of a nitrogenated heterocycle, such as tetrahydroquinoline or quinoline, is also necessary for the TopI inhibition to be maintained. In addition, no toxicity was observed when the non-cancerous lung fibroblast cell line (MRC5) was treated with the new phosphine sulphide gold(i) complexes prepared.

The topoisomerase I enzymatic inhibition of hybrid quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridines and quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-ones was investigated. First, the synthesis of these fused compounds was performed by intramolecular [4 + 2]-cycloaddition reaction of functionalized aldimines obtained by the condensation of 3-aminopyridine and unsaturated aldehydes affording corresponding hybrid 5-tosylhexahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine and tetrahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one compounds with good to high general yields. Subsequent dehydrogenation led to the corresponding more unsaturated dihydro (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine and (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one derivatives in quantitative yields. The new polycyclic products show excellent-good activity as topoisomerase I (TopI) inhibitors that lead to TopI induced nicking of plasmids. This is consistent with the compounds acting as TopI poisons resulting in the accumulation of trapped cleavage complexes in the DNA. The cytotoxic effect on cell lines A549, SKOV3 and on non-cancerous MRC5 was also screened. Tetrahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one 9 resulted the most cytotoxic compound with IC 50 values of 3.25 ± 0.91 μM and 2.08 ± 1.89 μM against the A549 cell line and the SKOV3 cell line, respectively. Also, hexahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine 8a and dihydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine 10a showed good cytotoxicity against these cell lines. None of the compounds presented cytotoxic effects against non-malignant pulmonary fibroblasts (MRC-5)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

This work describes the synthesis of hybrid tetrahydro-1,5-naphthyridine and 1,5-naphthyridine derivatives fused with heterocycles such as chromenes and chromen-2-ones or coumarins, which were synthesized in good to high general yields. The synthetic route involves an intramolecular [4 + 2]-cycloaddition reaction of functionalized aldimines obtained by the condensation of 3-aminopyridine and aldehydes containing a double or triple carbon-carbon bond in orto position and allows the selective generation of three stereogenic centers in a short, efficient and reliable synthesis. The subsequent dehydrogenation of the fused tetrahydrochromeno[4,3-b][1,5]naphthyridines and/or tetrahydrochromeno[4,3-b][1,5]naphthyridin-6-ones leads to the formation of the corresponding tetracyclic chromeno[4,3-b][1,5]naphthyridine derivatives and/or chromeno[4,3-b][1,5]naphthyridin-6-ones in quantitative yields. Some of the prepared products showed activity as inhibitors of Topoisomerase I (TopI). Additionally, the cytotoxic behavior of these compounds has been studied in cell lines derived from human lung adenocarcinoma (A549) and human ovarian carcinoma (SKOV03), and on non-cancerous lung fibroblasts cell line (MRC5) where, on the last ones, the absence of cytotoxicity was observed. 7-Phenyl-6H-6a,7,12,12a-tetrahydrochromeno[4,3-b][1,5]naphthyridine 5a showed excellent cytotoxic activity with a IC 50 value of 1.03 ± 0.30 μM against the A549 cell line and a IC 50 value of 1.75 ± 0.20 μM against the SKOV03 cell line. The obtained results point to these compounds as good antiproliferative candidates., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Heterocyclic compounds, such as hybrid tetrahydroquinoline and quinoline derivatives with phosphorated groups, have been prepared by multicomponent cycloaddition reaction between phosphorus-substituted anilines, aldehydes and styrenes. The antileishmanial activity of these compounds has been evaluated on both promastigotes and intramacrophagic amastigotes of Leishmania infantum. Good antileishmanial activity of functionalized tetrahydroquinolines 4a, 5a, 6b and quinoline 8b has been observed with similar activity than the standard drug amphotericin B and close selective index (SI between 43 and 57) towards L. infantum amastigotes to amphotericin B. Special interest shows tetrahydroquinolylphosphine sulfide 5a with an EC 50 value (0.61 ± 0.18 μM) similar to the standard drug amphotericin B (0.32 ± 0.05 μM) and selective index (SI = 56.87). In addition, compound 4c shows remarkable inhibition on Leishmania topoisomerase IB. Parallel theoretical study of stereoelectronic properties, application of docking-based virtual screening methods, along with molecular electrostatic potential and predictive druggability analyses are also reported., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

An efficient synthetic methodology for the preparation of phosphorus substituted bis-(3-indolyl)methane through a double nucleophilic addition of indole derivatives to an in situ generated α-iminophosphonate is reported. In addition, bis-(3-indolyl)methane substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines A549 (carcinomic human alveolar basal epithelial cell) and SKOV03 (human ovarian carcinoma)., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Visceral leishmaniasis is a parasitic disease that affects, among other areas, both sides of the Mediterranean Basin. The drugs classically used in clinical practice are pentavalent antimonials (Sb V ) and amphotericin B, which are nephrotoxic, require parenteral administration, and increasing drug resistance in visceral leishmaniasis has been observed. These circumstances justify the search of new families of compounds to find effective drugs against the disease. Eukaryotic type I DNA topoisomerase (TopIB) has been found essential for the viability of the parasites, and therefore represents a promising target in the development of an antileishmanial therapy. In this search, heterocyclic compounds, such as 1,5-naphthyridines, have been prepared by cycloaddition reaction between N-(3-pyridyl)aldimines and acetylenes and their antileishmanial activity on promastigotes and amastigote-infected splenocytes of Leishmania infantum has been evaluated. In addition, the cytotoxic effects of newly synthesized compounds were assessed on host murine splenocytes in order to calculate the corresponding selective indexes (SI). Excellent antileishmanial activity of 1,5-naphthyridine 19, 21, 22, 24 and 27 has been observed with similar activity than the standard drug amphotericin B and higher selective index (SI > 100) towards L. infantum amastigotes than amphotericin B (SI > 62.5). Special interest shows the 1,5-naphthyridine 22 with an IC 50 value (0.58 ± 0.03 μM) similar to the standard drug amphotericin B (0.32 ± 0.05 μM) and with the highest selective index (SI = 271.5). In addition, this compound shows remarkable inhibition on leishmanial TopIB. However, despite these interesting results, further studies are needed to disclose other potential targets involved in the antileishmanial effect of these novel compounds., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

This work describes the synthesis of 1,2,3,4-tetrahydroquinolinylphosphine oxides, phosphanes and phosphine sulfides as well as that of quinolinylphosphine oxides and phosphine sulfides, which were synthesized in good to high overall yield. The synthetic route involves a multicomponent reaction of (2-phosphine-oxide)-, 2-phosphine- or (2-phosphine-sulfide)-aniline, aldehydes and olefins and allows the selective generation of two stereogenic centres in a short, efficient and reliable synthesis. The selective dehydrogenation of 1,2,3,4-tetrahydroquinolinylphosphine oxides and phosphine sulfides leads to the formation of corresponding phosphorus substituted quinolines. Some of the products which were prepared showed excellent activity as topoisomerase I (Top1) inhibitors. In addition, prolonged effect of the most potent compounds is maintained with the same intensity even after 3 min of the beginning of the enzymatic reaction. The cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV03) and human embryonic kidney (HEK293) was also screened. 1,2,3,4-Tetrahydroquinolinylphosphine oxide 6g with an IC 50 value of 0.25 ± 0.03 μM showed excellent activity against the A549 cell line in vitro, while 1,2,3,4-tetrahydroquinolinylphosphane 9c with an IC 50 value of 0.08 ± 0.01 μM and 1,2,3,4-tetrahydroquinolinylphosphine sulfide derivative 10f with an IC 50 value of 0.03 ± 0.04 μM are more active against the A549 cell line. Moreover, selectivity towards cancer cell (A549) over non-malignant cells (MRC5) has been observed. According to their structure, they may be excellent antiproliferative candidates., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

In this work, we studied computationally the N-demethylation reaction of methylamine, dimethylamine, and trimethylamine as archetypal examples of primary, secondary, and tertiary amines catalyzed by high-field low-spin Fe-containing enzymes such as cytochromes P450. Using DFT calculations, we found that the expected C-H hydroxylation process was achieved for trimethylamine. When dimethylamine and methylamine were studied, two different reaction mechanisms (C-H hydroxylation and a double hydrogen atom transfer) were computed to be energetically accessible and both are equally preferred. Both processes led to the formation of formaldehyde and the N-demethylated substrate. Finally, as an illustrative example, the relative contribution of the three primary oxidation routes of tamoxifen was rationalized through energetic barriers obtained from density functional calculations and docking experiments involving CYP3A4 and CYP2D6 isoforms. We found that the N-demethylation process was the intrinsically favored one, whereas other oxidation reactions required most likely preorganization imposed by the residues close to the active sites.

Both experimental and computational studies for the cycloaddition reaction between N-(3-pyridyl)aldimines and acetylenes where 1,5-naphthyridines are obtained are reported. The reaction of benzaldimine with a methoxycarbonyl group in position 2 with phenyl acetylene, styrene, and indene afforded polycyclic isoindolone derivatives. The mechanism of reaction of N-(3-pyridyl)aldimines with olefins can be explained by an asynchronous [4+2] cycloaddition; in the case of acetylenes, the obtained results suggest a stepwise mechanism through a 3-azatriene.

The continuous need for the development of new small molecule anti-cancer drugs calls for easily accessible sensor systems for measuring the effect of vast numbers of new drugs on their potential cellular targets. Here we demonstrate the use of an optical DNA biosensor to unravel the inhibitory mechanism of a member of a new family of small molecule human topoisomerase I inhibitors, the so-called indeno-1,5-naphthyridines. By analysing human topoisomerase I catalysis on the biosensor in the absence or presence of added drug complemented with a few traditional assays, we demonstrate that the investigated member of the indeno-1,5-naphthyridine family inhibited human topoisomerase I activity by blocking enzyme-DNA dissociation. To our knowledge, this represents the first characterized example of a small molecule drug that inhibits a post-ligation step of catalysis. The elucidation of a completely new and rather surprising drug mechanism-of-action using an optical real time sensor highlights the value of this assay system in the search for new topoisomerase I targeting small molecule drugs.

The behavior of phosphinyl nitrosoalkenes with indole, pyrrole and 2,5-dimethylpyrrole is described. The reaction of nitrosoalkenes with indole leads to the formation of 3-substituted indoles. While a concerted asynchronous [4 + 2] cycloaddition process may explain the formation of 3-substituted indole when a methyl group is present at the 3-position of nitrosoalkene, the presence of a 3-methoxycarbonyl group at the same position of nitrosoalkene increases its electrophilic character, and both mechanisms, an electrophilic aromatic substitution and a [4 + 2] cycloaddition process, are predicted to be competitive, although thermodynamically the cycloaddition is favoured. Phosphinyl nitrosoalkenes react with pyrrole leading to the corresponding 2-substituted pyrroles, while the treatment of 2,5-dimethylpyrrole with these nitrosoalkenes gives rise to the formation of bicyclic 1,2-oxazines. The mechanism of the reaction of phosphinyl nitrosoalkenes with pyrrole and 2,5-dimethylppyrrole may be explained by an initial hetero-Diels-Alder cycloaddition in both cases, but only subsequent rearomatization in the case of pyrrole. Theoretical studies show very good agreement with the experimental findings and the proposed mechanisms.

Visceral leishmaniasis is a neglected disease of poor and developing countries. The current therapeutic approach is based on pentavalent antimonial (Sb V ) drugs and amphotericin B, both nephrotoxic and parenterally administered drugs. Therefore, there is a real need of new antileishmanial drugs. Eukaryotic type I DNA topoisomerases (TopIB) have been identified as druggable targets against leishmaniasis. These enzymes are involved in solving topological problems generated during replication, transcription and recombination of DNA. Leishmanial TopIB is a unique heterodimeric protein structurally different than that found in the mammalian host, thus making it an interesting target for drug discovery. Tetrahydro indeno-1,5-naphthyridines 5 and indeno[1,5]naphthyridines 6 were synthesized. The inhibition of Leishmania and human TopIB of these polycyclic heterocycles were studied and their antileishmanial activity on promastigotes and amastigote-infected splenocytes of Leishmania infantum were evaluated. In this regard, it is noteworthy that some of the prepared heterocycles, as compounds 6b, 6i and 5 h, showed selective inhibition of LtopIB while no inhibition of hTopIB was observed at evaluated conditions. In addition, the cytotoxic effects of newly synthesized compounds were assessed on host murine splenocytes in order to calculate the corresponding selective indexes (SI). Tetrahydro indeno-1,5-naphthyridines 5e and 5h showed good antileishmanial activity (IC 50 values of 0.67 ± 0.06 and 0.54 ± 0.17 μM) with similar activity than the standard drug amphotericin B (0.32 ± 0.05 μM) and even tetrahydro indeno-1,5-naphthyridine 5h showed higher (SI) towards L. Infantum amastigotes. Likewise, in the family of indeno-[1,5]-naphthyridines 6, compound 6b showed good antileishmanial activity (IC 50 value 0.74 ± 0.08 μM) and higher selective index (SI) towards L. Infantum amastigotes than amphotericin B., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

In an effort to establish new candidates with improved anticancer activity, we report here the synthesis of various series of 7H-indeno[2,1-c][1,5]-naphthyridines and novel 7H-indeno[2,1-c][1,5]-naphthyridine-7-ones and 7H-indeno[2,1-c][1,5]-naphthyridine-7-ols. Most of the products which were synthesized were able to inhibit Topoisomerase I activity. Moreover, in vitro testing demonstrated that a subset of the products exhibited a cytotoxic effect on cell lines derived from human breast cancer (BT 20), human lung adenocarcinoma (A 549), or human ovarian carcinoma (SKOV3)., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A regioselective addition of isocyanates to fluoroalkylated α,β-unsaturated imines 1 is described. Fluoroalkyl-substituted triazinane-2,4-diones 4 are obtained by the reaction of phenyl isocyanate with fluorinated imines 1, while fluorinated dihydropyridin-2(1H)-ones 7 are prepared when tosyl isocyanate is used. Tetrahydro-pyridin-2(1H)-one 10 is obtained by catalytic reduction of dihydropyridin-2(1H)-one 7. Computational studies are performed to explain the different behaviors of both isocyanates and the mechanisms of the processes.

The synthesis of a variety of phenyl- and indeno-1,5-naphthyridine derivatives as new substrates with anticancer activity is described. Several of the prepared products were addressed to in vitro anticancer screening which indicated that some of them exhibited inhibitory effect of Top1 and antiproliferative activity against human colon cancer cells (COLO 205).

The functionalized polyfluorophosphorylated 1-azadienes I have been prepared by a Wittig reaction of ethyl glyoxalate and perfluorophosphorylated conjugated phosphoranes, obtained by reaction of phosphazenes and fluorinated acetylenic phosphonates. Subsequent reduction of both carbon-carbon and carbon-nitrogen double bonds of these 1-azadienes I affords the fluorine-containing β-aminophosphonates II, with the syn β-aminophosphonate being obtained as the major diastereoisomer. Base-mediated cyclocondensation of a diastereomeric mixture of aminophosphonates II leads exclusively to a new type of functionalized trans-γ-lactams III in a diastereoselective way. A computational study has also been used to explain the observed diastereoselectivity of these reactions.

Phosphorylated nitroso alkenes react with cyclic dienes such as cyclopentadiene or cyclohexadiene to afford hetero Diels-Alder-type cycloadducts where the nitroso alkene participates as dienophile component and the cyclic olefin acts as the 4π-electron (diene) system. Subsequent aza-Cope rearrangement affords highly functionalized 5,6-dihydro-4H-1,2-oxazines. Conversely, the reaction of TMS-substituted cyclopentadiene (dienophile) with nitroso alkenes as heterodienes leads directly to bicyclic 1,2-oxazines. Theoretical studies are in agreement with the experimental results and with the new aza-Cope rearrangement proposed.

Aza-Wittig reaction of N-vinylic phosphazenes (1,2 addition), derived from diphenylmethylphosphine or derived from trimethylphosphine with alpha,beta-unsaturated aldehydes, leads to the formation of 3-azatrienes through a [2 + 2]-cycloaddition-cycloreversion sequence. The presence of an alkyl substituent in position 3 of N-vinylic phosphazenes increases the steric interactions, and [4 + 2] periselectivity (1,4 addition) is observed. Reaction of azatrienes with alpha,beta-unsaturated aldehydes yields pyridines.

The mechanism of the aza-Wittig reaction between phosphazenes and aldehydes has been studied computationally, using DFT methods (B3LYP/6-31G level), and experimentally. It has been found that the reaction consists of a tandem [2+2] cycloaddition-cycloreversion sequence in which pi and sigma orbitals as well as lone pairs are involved. Both [2+2] processes take place via thermally allowed supra-supra mechanisms. P-trimethyl-lambda(5)-phosphazenes are predicted to be more reactive than their P-triphenyl analogues. The stereochemical outcome of the whole reaction depends only on the second step, because conformational changes in the intermediate 1,3,2-lambda(5)-oxazaphosphazetidines have a much lower activation energy than the second [2+2] cycloreversion reaction. Preferential or exclusive formation of the corresponding (E)-imines is predicted.

Reaction of phosphazenes derived from aminophosphonates with acetylenic esters leads to conjugated phosphorus ylides. The formation of these stabilized ylides is explained through a [2 + 2] cycloaddition reaction of the P = N linkage of the phosphazene (1,2-addition) and the triple bond of the acetylenic ester followed by ring opening of the azaphosphete intermediate. However, in the case of N-vinylic phosphazenes, the phosphazenes derived from triphenyl- and trimethyl-phosphine react as enamines (1,4-addition) with diacetylenic esters, whereas in phosphazenes derived from trimethylphosphine a 1,2-addition of ethyl propiolate to the P = N linkage of the phosphazene is produced.