Photoproperties of favipiravir and its 6-substituted analogues: fluorescence controlled through halogen substitution and tautomerism.

Herein, we have showed the photophysical properties of favipiravir and its 6-substituted analogues. Also, we interpreted the origin of fluorescence of favipiravir and its 6-substituted analogues as a function of tautomerism modulation in ground and excited states. Favipiravir, the 6-fluorine derivative, showed the best photophysical profile, exhibiting a dominant emission wavelength of 430 nm, a high quantum yield (Q.Y.) of 1.0 and a long-lived state (10 ns). Its analogues also showed a maximum emission at 430 nm, but their Q.Y. values were 5-fold lower than that found for favipiravir, decreasing as a function of 6-substitution as follows: F > Cl > Br > I > H. Pyrazines bearing the least electronegative 6-substituent (X = Br, I, H) showed an extra lifetime, which was shorter (0.2-0.3 ns) and less abundant (>15%) than the main lifetime (10 ns, 85%). Further 2D excitation-emission matrix and solvent studies supported that these 3-hydroxy-2-pyrazinecarboxamides present two emissive states. The first of them (λem = 430 nm), which was the most abundant, most fluorescent and long-lived state, was characterized as "locally excited" (LE). Its fluorescence was favored with an increase of the hydrogen-donor nature of the solvent and for pyrazines having a high enolic characteristic. Thus, the high LE-fluorescence of these types of pyrazines depends on the keto-tautomerization of the ground state using a protic solvent and its feasible enol-tautomerization upon excitation. Finally, the second excited state (λem = 536 nm) was suggested as an excited-state intramolecular proton-transfer (ESIPT), and it was observed only, although discretely, for pyrazines bearing the least electronegative 6-substituent.

In vitro antiviral activity of favipiravir and its 6- and 3-O-substituted derivatives against coronavirus: Acetylation leads to improvement of antiviral activity.

Favipiravir is currently approved for the treatment of the influenza virus and has shown encouraging results in terms of antiviral capacity in clinical studies against severe acute respiratory syndrome coronavirus 2. Favipiravir is a prodrug, where its favipiravir-ribofuranosyl-5B-triphosphate metabolite is capable of blocking RNA replication of the virus. However, the antiviral efficiency of favipiravir is limited by two factors: (i) low accumulation in plasma and rapid excretion/elimination post-administration and (ii) low conversion rate into the active metabolite. To tackle these problems, herein, we have designed new favipiravir analogues focusing on the replacement of the fluorine atom at the 6-position by halogen or hydrogen atoms and 3-O-functionalization with labile groups. The first type of functionalization seeks to increase the antiviral activity because of the better ability of the keto-tautomer as a function of the halogen, and it is hypothesized that the keto-tautomer tends to promote the formation of the ribofuranosyl-5B-triphosphate (RTP) metabolite. Meanwhile, the second type of functionalization seeks to promote lipophilicity and increase accumulation in cells. From the in vitro antiviral activity against two coronavirus models (bovine and human 229E), it was identified that the replacement did not improve the antiviral activity against both the models, which seems to be attributable to the low water solubility of these new 6-functionalized analogues. Meanwhile, with 3-O-functionalization, acetylation provided the most active compounds with higher half-maximal inhibitory concentration and selectivity than favipiravir, whereas benzylation/methanosulfonation yielded the least active compounds. In summary, acetylation is found to be a convenient functionalization to enhance the antiviral profile of favipiravir.

Tautomerism and Rotamerism of Favipiravir and Halogenated Analogues in Solution and in the Solid State.

Favipiravir is an important selective antiviral against RNA-based viruses, and currently, it is being repurposed as a potential drug for the treatment of COVID-19. This type of chemical system presents different carboxamide-rotameric and hydroxyl-tautomeric states, which could be essential for interpreting its selective antiviral activity. Herein, the tautomeric 3-hydroxypyrazine/3-pyrazinone pair of favipiravir and its 6-substituted analogues, 6-Cl, 6-Br, 6-I, and 6-H, were fully investigated in solution and in the solid state through ultraviolet-visible, 1H nuclear magnetic resonance, infrared spectroscopy, and X-ray diffraction techniques. Also, a study of the gas phase was performed using density functional theory calculations. In general, the keto-enol balance in these 3-hydroxy-2-pyrazinecarboxamides is finely modulated by external and internal electrical variations via changes in solvent polarity or by replacement of substituents at position 6. The enol tautomer was prevalent in an apolar environment, whereas an increase in the level of the keto tautomer was favored by an increase in solvent polarity and, even moreso, with a strong hydrogen-donor solvent. Keto tautomerization was favored either in solution or in the solid state with a decrease in 6-substituent electronegativity as follows: H ≫ I ≈ Br > Cl ≥ F. Specific rotameric states based on carboxamide, "cisoide" and "transoide", were identified for the enol and keto tautomer, respectively; their rotamerism is dependent on the tautomerism and not the aggregation state.

One-step synthesis of favipiravir from Selectfluor® and 3-hydroxy-2-pyrazinecarboxamide in an ionic liquid.

Favipiravir is an important selective antiviral that emerged as an alternative against COVID-19 during the pandemic. Its synthesis has gained great interest and the conventional strategies proceed through multiple-step protocols (6-7 reaction steps), which involve, in addition, several drawbacks with global yields, lower than 34%. Herein, a simple, economical, eco-friendly and scalable (1 g) one-step protocol for the synthesis of favipiravir from the direct fluorination of the available 3-hydroxy-2-pyrazinecarboxamide with Selectfluor® is reported. The reaction proceeds easily in BF4-BMIM through a simple operational work-up, affording the favipiravir with a yield of 50% without the need of a special catalyst/additive. The key point of the present strategy was the use of the ionic liquid of BF4-BMIM, which helps to minimize the several chemical limitations derived from 3-hydroxy-2-pyrazinecarboxamide as a substrate for the direct Selectfluor-mediated fluorination. All these chemical reactivity aspects are also discussed in detail.

Exploring binding chemistry of alkali/alkaline earth cations in solution through modulation of intramolecular charge-transfer in an excited ambidentate organic fluorophore.

Studying the metal-ligand monoligation of alkali/alkaline earth metals (AMs) in solution represents a significant challenge due to the low stabilization of their complexes and the absence of an effective strategy to identify this type of weak binding. Herein, we show that the modulation of the intramolecular charge-transfer (ICT) in an excited ambidentate organic fluorophore is a convenient strategy to characterize the binding chemistry of AM cations in solution through simple steady-state fluorescence and fluorescence lifetime measurements. The key points of the fluorophore as a metal-binding probe were the location of diverse coordination functionalities with different binding abilities (ionic-, pseudo-covalent- and non-covalent-probes) along the donor-acceptor (D-A) chain and the occurrence of an intramolecular charge-transfer (ICT) mechanism upon excitation. The binding of these functionalities with AM-cations generated selective and specific fluorescence responses, which were quantifiable and allowed us to recognize the primary, secondary and tertiary interactions for all the AM cations in the solution. The relative binding affinities for each one of the functionalities with AM cations was estimated, and a general and consistent perspective of the binding of AMs as a function of their location in the Periodic Table, hardness property and ionic radius was established. The binding preferences of the AM cations were supported by DFT calculations. Our strategy allowed us to validate the binding dynamics of AMs in solution for three types of key ligations, which opens a new perspective to recognize weak intermolecular interactions derived from acidic species and rationally design selective AM-cation probes using an ICT-based ambidentate organic fluorophore.

A New Class of Task-Specific Imidazolium Salts and Ionic Liquids and Their Corresponding Transition-Metal Complexes for Immobilization on Electrochemically Active Surfaces.

Adding to the versatile class of ionic liquids, we report the detailed structure and property analysis of a new class of asymmetrically substituted imidazolium salts, offering interesting thermal characteristics, such as liquid crystalline behavior, polymorphism or glass transitions. A scalable general synthetic procedure for N-polyaryl-N'-alkyl-functionalized imidazolium salts with para-substituted linker (L) moieties at the aryl chain, namely [LPhm ImH R]+ (L=Br, CN, SMe, CO2 Et, OH; m=2, 3; R=C12 , PEGn ; n=2, 3, 4), was developed. These imidazolium salts were studied by single-crystal X-ray diffraction (SC-XRD), NMR spectroscopy and thermochemical methods (DSC, TGA). Furthermore, these imidazolium salts were used as N-heterocyclic carbene (NHC) ligand precursors for mononuclear, first-row transition metal complexes (MnII , FeII , CoII , NiII , ZnII , CuI , AgI , AuI ) and for the dinuclear Ti-supported Fe-NHC complex [(OPy)2 Ti(OPh2 ImC12 )2 (FeI2 )] (OPy=pyridin-2-ylmethanolate). The complexes were studied concerning their structural and magnetic behavior via multi-nuclear NMR spectroscopy, SC-XRD analyses, variable temperature and field-dependent (VT-VF) SQUID magnetization methods, X-band EPR spectroscopy and, where appropriate, zero-field 57 Fe Mössbauer spectroscopy.

High CT-Fluorophore Featuring a Basic Moiety into D-A Chain as a pKa Probe.

The determination of acidity represents a significant challenge within fluorometry, and no effective strategy has been developed successfully yet. It is attributed to the fact that acidity tends to be enhanced upon excitation, giving, in general, an overestimation of the ionization constant, pKa. Herein, we developed a strategy for pKa estimation of Brønsted acids in solution through fluorometry by using a convenient pKa probe, N1-aryl-7-methoxy-2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one. It allowed us to obtain a linear log KSV versus pKa correlation derived from the selective quenching response of the probe by an interaction with different Brønsted acids. The key points of N1-aryl-7-methoxy-2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one as a pKa probe were (i) the location of a weak basic moiety in the donor-acceptor chain of the fluorophore, which favors a selective quenching of the intramolecular charge-transfer process according to the acidity of acid, and (ii) the high CT character upon excitation that promotes higher quenching magnitudes and favors a wider pKa range (19.5pKa) for the log KSV versus pKa correlation. Other key principles were to delimit the study to pure proton transfer and nonfluorescent acids, which allowed restricting the quenching response to a process dependent mainly on the acid-base equilibrium. All these findings open a new perspective as a proof of concept to design effective fluorescent pKa probes.

Anticancer potential of new 3-nitroaryl-6-(N-methyl)piperazin-1,2,4-triazolo[3,4-a]phthalazines targeting voltage-gated K+ channel: Copper-catalyzed one-pot synthesis from 4-chloro-1-phthalazinyl-arylhydrazones.

A series of six 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines were prepared through a facile and efficient one-pot copper-catalyzed procedure from 4-chloro-1-phthalazinyl-arylhydrazones with relatively good yields (62-83%). The one-pot copper-catalytic procedure consists of two simultaneous reactions: (i) a direct intramolecular dehydrogentaive cyclization between ylidenic carbon and adjacent pyrazine nitrogen to form 1,2,4-triazolo ring and, (ii) a direct N-amination on carbon-chlorine bond. Then, an in vitro anticancer evaluation was performed for the synthesized compounds against five selected human cancer cells (A549, MCF-7, SKBr3, PC-3 and HeLa). The nitro-derivatives were significantly more active against cancer strains than against the rest of tested compounds. Specifically, compound 8d was identified as the most promising anticancer agent with significant biological responses and low relative toxicities on human dermis fibroblast. The cytotoxic effect of compound 8d was more significant on PC3, MCF-7 and SKBr3 cancer cells with low-micromolar IC50 value ranging from 0.11 to 0.59 µM, superior to Adriamycin drug. Mechanistic experimental and theoretical studies demonstrated that compounds 8d act as a K+ channel inhibitor in cancer models. Further molecular docking studies suggest that the EGFR Tyrosine Kinase enzyme may be a potential target for the most active 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines.

2-Aryl-quinazolin-4(3H)-ones as an inhibitor of leishmania folate pathway: In vitro biological evaluation, mechanism studies and molecular docking.

To identify new agents for the American Cutaneous Leishmaniasis treatment, a series of 2-aryl-quinazolin-4(3H)-ones were tested against L. mexicana, L. braziliensis and L. amazonensis parasites as potential inhibitor of folic metabolism pathway. In general, the L. braziliensis and L. mexicana promastigote parasites were more sensitive to the action of the quinazolinones than L. amazonensis. The most active derivatives showed low-micromolar EC50 ranging from 4 to 10 µM, being 1.3 to 4 fold more potent than glucantime reference drug. A complete in vitro evaluation on intracellular amastigote, axenic amastigote and murine peritoneal macrophage were performed for the most active derivatives. The compounds 2j, 2h, 2t and 2u displayed acceptable responses against intracellular amastigote compared to reference drug, excellent antileishmanial activities against axenic amastigote (LD50 ranging from 1 to 4 µM) and relative low toxicities on peritoneal macrophages. To validate the efficacy of these four derivatives, an in vitro evaluation was performed against an antimony-resistant amastigote strain; identifying to 2h and 2u as promising antileishmanial leads for further pharmacokinetics and in vivo studies. Experimental mechanism assays putted in evidences that the most active compounds act as folate inhibitor. A tentative molecular docking on pteridine reductase 1 (PTR1) enzyme showed that the most active quinazolinones 2j and 2t are located in almost identical place compared with methotrexate reference into active site.

Antileismanial activity, mechanism of action study and molecular docking of 1,4-bis(substituted benzalhydrazino)phthalazines.

To identify new agents for the treatment of American cutaneous leishmaniasis, a series of eight 1,4-bis(substituted benzalhydrazino)phthalazines was evaluated against Leishmania braziliensis and Leishmania mexicana parasites. These compounds represent a disubstituted version of the 1-chloro-4-(monoaryl/heteroarylhydranizyl)phthalazine that exhibited a significant response against L. braziliensis according to our previous findings. Two disubstituted phthalazines 3b and 3f were identified as potential antileishmanial agents against L. braziliensis parasites, exhibiting a submicromolar IC50 response of 2.37 and 7.90 µM on the promastigote form, and of 1.82 and 4.56 µM against intracellular amastigotes, respectively. In particular, compound 3b showed interesting responses against amastigote isolates from reference, glucantime-resistant and clinical human strains, which were by far superior to the biological response found for the glucantime drug. With regard to the toxicity results, both 3b and 3f exhibited moderate LD50 values against murine macrophages (BMDM), with good selectivity indexes on promastigotes and intracellular amastigotes of L. braziliensis. A comparison of biological response was established between the monosubstituted and disubstituted versions of these benzalhydrazino-phthalazines. Easy synthetic procedure and significant response against amastigote strains including against resistant lines made compound 3b a potential candidate for further pharmacokinetic and in vivo experiments as antileishmanial agent, and as a platform for further structural optimization. Mechanism-of-action studies and molecular docking simulations discarded to inhibition of superoxide dismutase as possible mode of action.

Identification of dehydroxy isoquine and isotebuquine as promising antileishmanial agents.

Traditional antimalarial drugs based on 4-aminoquinolines have exhibited good antiproliferative activities against Leishmania parasites; however, their clinical use is currently limited. To identify new 4-aminoquinolines to combat American cutaneous leishmaniasis, we carried out a full in vitro evaluation of a series of dehydroxy isoquines and isotebuquines against two Leishmania parasites such as Leishmania braziliensis and Leishmania mexicana. First, the antiproliferative activity of the quinolines was studied against the promastigote forms of L. braziliensis and L. mexicana parasites, finding that five of them exhibited good antileishmanial responses with micromolar IC50 values ranging from 3.84 to 10 µM. A structure-activity relationship analysis gave evidence that a piperidine or a morpholine attached as N-alkyamino terminal substituent as well as the inclusion of an extra phenyl ring attached at the aniline ring of the isotebuquine core constitute important pharmacophores to generate the most active derivatives, with antileishmanial responses by far superior to those found for the reference drug, glucantime. All compounds showed a relatively low toxicity on human dermis fibroblasts, with CC50 ranging from 69 to >250 µM. The five most active compounds displayed moderate to good antileishmanial activity against the intracellular amastigote form of L. braziliensis, compared to the reference drug. In particular, compound 2j was identified as the most potent agent against antimony-resistant amastigotes of L. braziliensis with acceptable biological response and selectivity, emerging as a promising candidate for further in vivo antileishmanial evaluation. Diverse mechanism-of-action studies and molecular docking simulations were performed for the most active 4-aminoquinoline.

Antileishmanial activity, structure-activity relationship of series of 2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-ones.

Trifluoromethyl-substituted quinolones and their analogues have emerged as an interesting platform in the last 6 years to design antiparasite agents. Many of their derivatives have been demonstrated to display excellent efficacy against flagellate parasites such as Plasmodium spp. In order to identify new analogues of trifluoromethyl-substituted quinolones to treat the American cutaneous leishmaniasis, we evaluated the antiproliferative activity of a series of 2-(trifluoromethyl)benzo[b]-[1,8]naphthyridin-4(1H)-ones on the Leishmania braziliensis and Leishmania mexicana parasites. The mentioned derivatives have never been evaluated against any parasite strain. In general, an in vitro evaluation on L.(L)mexicana and L.(V)braziliensis showed that L.(L)mexicana was more sensitive to the action of the compounds than L.(V)braziliensis, either in the promastigote or in the amastigote form. Five compounds exhibited moderate efficacy against L.(L)mexicana promastigotes, with IC50 values ranging from 9.65 to 14.76 µM. From the mentioned molecules, three compounds, 1e, 1f, and 1h, showed a discrete response against axenic and intracellular amastigotes, with LD50 values between 19 and 24 µM. Moreover, an in vitro evaluation was performed on an antimony-resistant amastigote strain and a human isolate amastigote strain. These three compounds showed discrete toxicity on peritoneal macrophages; however, their relatively good antiamastigote response compared to the drug glucantime promoted our trifluoromethyl-substituted benzo[b][1,8]naphthyridin-4(1H)-ones as a potential platform to design potent antileishmanial agents.

Aryl- or heteroaryl-based hydrazinylphthalazine derivatives as new potential antitrypanosomal agents.

A series of twenty phthalazinyl-hydrazones were synthesized and tested as potential anti-Trypanosoma cruzi agents. The phthalazines containing 5-nitroheteroaryl moiety 3l and 3m displayed an excellent in vitro antitrypanosomal profile, exhibiting low micromolar EC50 values against proliferative epimastigote of T. cruzi and minimal toxicity toward Vero cells. These derivatives were more potent than the reference drug benznidazole against the epimastigote stage of the parasite. Structure-property analysis indicates that the highly conjugated 5-nitroheteroaryl moiety connected to the phthalazin scaffold play an important role in the antichagasic activity of these phthalazines. The decrease on the mitochondrial dehydrogenase activity and significant ROS production found for the parasites treated with 3l and 3m suggest that both nitro-derivatives can act through an oxidative stress mechanism.

Synthesis, ß-hematin inhibition studies and antimalarial evaluation of dehydroxy isotebuquine derivatives against Plasmodium berghei.

Diverse dehydroxy-isotebuquine derivatives were prepared by using a five step synthetic sequence in good yields. All these new 4-aminoquinolines were evaluated as inhibitors of haemozoin formation, where most of them showed a significant inhibition value (% IHF >97). The best inhibitors were tested in vivo as potential antimalarials in mice infected with Plasmodium berghei ANKA chloroquine susceptible strain, three of them (11b, 11d and 11h) displayed an antimalarial activity comparable to that of chloroquine.

C-H Bond Functionalization of N-Heteroarenes Mediated by Selectfluor.

Herein, recent developments for Selectfluor-mediated C-H functionalization of N-heteroarenes are described. This type of C-H bond activation is an attractive and competitive alternative to traditional methodologies, allowing the functionalization of a variety of chemical functions. In addition, Selectfluor is a more sustainable and economically accessible oxidant compared with expensive/toxic metals or hazardous peroxides. For a practical understanding, the current review classified systematically the reported strategies in four subsections as follows: (1) carbon-carbon formation, (2) carbon-nitrogen bond formation, (3) carbon-chalcogen bond, and (4) carbon-halogen bond formation. Mechanistic aspects and reaction conditions are fully discussed to provide an understanding of the aspects that govern C-H functionalization in N-heteroarenes mediated by Selectfluor.

Optimization of the 2-arylquinazoline-4(3H)one scaffold for a selective and potent antitrypanosomal agent: modulation of the mechanism of action through chemical functionalization.

We sought to identify a potent and selective antitrypanosomal agent through modulation of the mechanism of action of a 2-arylquinazoline scaffold as an antitrypanosomal agent via chemical functionalization at the 4-position. We wished to use the: (i) susceptibility of trypanosomatids towards nitric oxide (NO) and reactive oxygen species (ROS); (ii) capacity of the 4-substituted quinazoline system to act as an antifolate agent. Three quinazolin-based moieties that differed from each other by having at the 4-position key pharmacophores targeting the induction of NO and ROS production were evaluated in vitro against Leishmania infantum and Trypanosoma cruzi parasites and their modes of action were explored. Replacement of an oxygen moiety at the 4-position of the antifolate 2-arylquinazolin-4(3H)one by hydrazinyl and 5-nitrofuryl-hydrazinyl pharmacophores enhanced antitrypanosomatid activity significantly due to promotion of an additional mechanism beyond the antifolate response such as NO or ROS production, respectively. Among the three types of chemical functionalization, the 5-nitrofuryl-hydrazinyl moiety generated the most potent compounds. Compound 3b was a potential candidate thanks to its sub-micromolar response against the promastigotes/amastigotes of L. infantum and epimastigote of T. cruzi, moderate toxicity on macrophages (J774.1), good selectivity index (∼15.1-17.6) and, importantly, non-mutagenic effects. 2-Arylquinazoline could be an attractive platform to design new anti-trypanosomatid agents with the use of key pharmacophores.

Antimalarial Activity of Highly Coordinative Fused Heterocycles Targeting ß-Hematin Crystallization.

The ß-hematin formation is a unique process adopted by Plasmodium sp. to detoxify free heme and represents a validated target to design new effective antimalarials. Most of the ß-hematin inhibitors are mainly based on 4-aminoquinolines, but the parasite has developed diverse defense mechanisms against this type of chemical system. Thus, the identification of other molecular chemical entities targeting the ß-hematin formation pathway is highly needed to evade resistance mechanisms associated with 4-aminoquinolines. Herein, we showed that the highly coordinative character can be a useful tool for the rational design of antimalarial agents targeting ß-hematin crystallization. From a small library consisting of five compound families with recognized antitrypanosomatid activity and coordinative abilities, a group of tetradentate 1,4-disubstituted phthalazin-aryl/heteroarylhydrazinyl derivatives were identified as potential antimalarials. They showed a remarkable curative response against Plasmodium berghei-infected mice with a significant reduction of the parasitemia, which was well correlated with their good inhibitory activities on ß-hematin crystallization (IC50 = 5-7 µM). Their in vitro inhibitory and in vivo responses were comparable to those found for a chloroquine reference. The active compounds showed moderate in vitro toxicity against peritoneal macrophages, a low hemolysis response, and a good in silico ADME profile, identifying compound 2f as a promising antimalarial agent for further experiments. Other less coordinative fused heterocycles exhibited moderate inhibitory responses toward ß-hematin crystallization and modest efficacy against the in vivo model. The complexation ability of the ligands with iron(III) was experimentally and theoretically determined, finding, in general, a good correlation between the complexation ability of the ligand and the inhibitory activity toward ß-hematin crystallization. These findings open new perspectives toward the rational design of antimalarial ß-hematin inhibitors based on the coordinative character as an alternative to the conventional ß-hematin inhibitors.

Synthesis and Antitrypanosomal and Mechanistic Studies of a Series of 2-Arylquinazolin-4-hydrazines: A Hydrazine Moiety as a Selective, Safe, and Specific Pharmacophore to Design Antitrypanosomal Agents Targeting NO Release.

Nitric oxide (NO) represents a valuable target to design antitrypanosomal agents by its high toxicity against trypanosomatids and minimal side effects on host macrophages. The progress of NO-donors as antitrypanosomal has been restricted by the high toxicity of their agents, which usually is based on NO-heterocycles and metallic NO-complexes. Herein, we carried out the design of a new class of NO-donors based on the susceptibility of the hydrazine moiety connected to an electron-deficient ring to be reduced to the amine moiety with release of NO. Then, a series of novel 2-arylquinazolin-4-hydrazine, with the potential ability to disrupt the parasite folate metabolism, were synthesized. Their in vitro evaluation against Leishmania and Trypanosoma cruzi parasites and mechanistic aspects were investigated. The compounds displayed significant leishmanicidal activity, identifying three potential candidates, that is, 3b, 3c, and 3f, for further assays by their good antiamastigote activities against Leishmania braziliensis, low toxicity, non-mutagenicity, and good ADME profile. Against T. cruzi parasites, derivatives 3b, 3c, and 3e displayed interesting levels of activities and selectivities. Mechanistic studies revealed that the 2-arylquinazolin-4-hydrazines act as either antifolate or NO-donor agents. NMR, fluorescence, and theoretical studies supported the fact that the quinazolin-hydrazine decomposed easily in an oxidative environment via cleavage of the N-N bond to release the corresponding heterocyclic-amine and NO. Generation of NO from axenic parasites was confirmed by the Griess test. All the evidence showed the potential of hydrazine connected to the electron-deficient ring to design effective and safe NO-donors against trypanosomatids.

Photo-Induced Partially Aromatized Intramolecular Charge Transfer.

Diverse models of intramolecular charge transfer (ICT) have been proposed for interpreting the origin of the charge-transfer (CT) state in donor-acceptor (D-A) dyes. However, a large variety of fused-heterocyclic dyes containing a pseudo-aromatic ring in the rigid structure have shown to be incompatible with them. To approximate a solution within the ICT concept, we reported a novel ICT model called partially aromatized intramolecular charge transfer (PAICT). PAICT involves the generation of a CT state from an ICT that occurred within a pre-excited D-A fused-heterocyclic structure possessing a pseudo-aromatic or unstable aromatic ring as the acceptor moiety. The model was proposed from the multiple-emissive mesomeric D-A N1-aryl-2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one, whose excited mesomeric states, which are defined by the aromatic and pseudo-aromatic forms of the pyrindin-4(1H)-one ring, led to a common partial aromatized CT state upon excitation via PAICT. The latter was supported through theoretical calculations on the excited mesomeric states, one-dimensional (1D) and two-dimensional (2D) excitation-emission measurements in different solvents, and the detection of three excited states by lifetime measurements upon 370 nm excitation. The existence of mesomerism was supposed from: (i) two overlapping bands at 370-390 (or 400-420 nm) in UV-vis spectra, (ii) the direct interaction between the pyridinic nitrogen of one molecule and the carbonylic oxygen of the other found in the solid state and, (iii) the detection of three excited states by lifetime measurements. The PAICT opens new perspectives for interpreting the charge-transfer phenomenon in fused-heterocyclic dyes, in particular, those containing a pseudo-aromatic or unstable aromatic ring as an acceptor moiety.

Fused Heteroaromatic Rings via Metal-Mediated/Catalyzed Intramolecular C-H Activation: A Comprehensive Review.

The present review highlights the most important recent contributions toward the synthesis of functionalized fused heteroaromatic rings via intramolecular C-H activation mediated or catalyzed by transition metals. This type of reaction constitutes a versatile strategy to obtain a great variety of fused heterocyclic systems through the formation of carbon-carbon (C-C) and C-heteroatom bonds from direct coupling between two adjacent C-H bonds or C-H/H-X bonds. The  revision is focused on the synthesis of fused heterocycles through two chemical processes: (1) metal-catalyzed intramolecular oxidative C-H activation, and (2) intramolecular C-H activation mediated by metallic Lewis acids.