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 N 1 -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.
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 NOheterocycles 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 2arylquinazolin-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.
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.
The β-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 β-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 β-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 β-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 β-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 β-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 β-hematin crystallization. These findings open new perspectives toward the rational design of antimalarial β-hematin inhibitors based on the coordinative character as an alternative to the conventional β-hematin inhibitors.
The modulation of the photo-induced proton coupled electron-transfer (PCET) mechanisms is a topic of great interest by its pivotal role in energy-transfer processes, development of fuel cells and activation of...
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