Exploring the Antibacterial and Antiparasitic Activity of Phenylaminonaphthoquinones-Green Synthesis, Biological Evaluation and Computational Study.

Organic compounds with antibacterial and antiparasitic properties are gaining significance for biomedical applications. This study focuses on the solvent-free synthesis (green synthesis) of 1,4-naphthoquinone or 2,3-dichloro-1,4-naphthoquinone with different phenylamines using silica gel as an acid solid support. The study also includes in silico PASS predictions and the discovery of antibacterial and antiparasitic properties of phenylaminonaphthoquinone derivatives 1-12, which can be further applied in drug discovery and development. These activities were discussed in terms of molecular descriptors such as hydrophobicity, molar refractivity, and half-wave potentials. The in vitro antimicrobial potential of the synthesized compounds 1-12 was evaluated against a panel of six bacterial strains (three Gram-positive: Staphylococcus aureus, Proteus mirabilis, and Enterococcus faecalis; and three Gram-negative bacteria: Escherichia coli, Salmonella typhimurium, and Klebsiella pneumoniae). Six compounds (1, 3, 5, 7, 10, and 11) showed better activity toward S. aureus with MIC values between 3.2 and 5.7 µg/mL compared to cefazolin (MIC = 4.2 µg/mL) and cefotaxime (MIC = 8.9 µg/mL), two cephalosporin antibiotics. Regarding in vitro antiplasmodial activity, compounds 1 and 3 were the most active against the Plasmodium falciparum strain 3D7 (chloroquine-sensitive), displaying IC50 values of 0.16 and 0.0049 µg/mL, respectively, compared to chloroquine (0.33 µg/mL). In strain FCR-3 (chloroquine-resistant), most of the compounds showed good activity, with compounds 3 (0.12 µg/mL) and 11 (0.55 µg/mL) being particularly noteworthy. Additionally, docking studies were used to better rationalize the action and prediction of the binding modes of these compounds. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed.

Modeling the alkylation of amines with alkyl bromides: explaining the low selectivity due to multiple alkylation.

CONTEXT: Nucleophilic substitution reactions of aliphatic amines with alkyl halides represent a simple and direct mechanism for obtaining higher-order aliphatic amines. However, it is well known that these reactions suffer from low selectivity due to multiple alkylations, which is attributed to the higher reactivity of the newly formed amine. In order to provide a detailed explanation for this kind of system, we have investigated the reactivity of primary and secondary amines with 1-bromopropane and 2-bromopropane. The free energy profile in acetonitrile solution was obtained and a detailed microkinetic analysis was needed to analyze this complex reaction system. We have found that the product of the first alkylation is an ion pair corresponding to the protonated secondary amine and the bromide ion, which can transfer the proton to the reactant primary amine. Then, the newly formed secondary amine can also react, leading to a second alkylation to produce a tertiary protonated amine. Our modeling points out that both the proton transfer equilibria and the similar reactivity of the primary and secondary amines produce reduced selectivity. The proton transfer equilibria also contribute to slowing down the kinetics of the first alkylation. METHODS: The exploration of the mechanism was done by geometry optimization using the CPCM/X3LYP/ma-def2-SVP method, followed by harmonic frequency calculation at this same level of theory. A composite approach was used to obtain the free energy profile, using the more accurate ωB97X-D3/ma-def2-TZVPP level of theory for electronic energy and the SMD model for the solvation free energy. These calculations were performed with the ORCA 4 program. The detailed microkinetic analysis was done using the Kintecus program.

Green Synthesis and Electrochemical Properties of Mono- and Dimers Derived from Phenylaminoisoquinolinequinones.

In the search for new quinoid compounds endowed with potential anticancer activity, the synthesis of novel heterodimers containing the cytotoxic 7-phenylaminoisoquinolinequinone and 2-phenylaminonaphthoquinone pharmacophores, connected through methylene and ethylene spacers, is reported. The heterodimers were prepared from their respective isoquinoline and naphthoquinones and 4,4'-diaminodiphenyl alkenes. The access to the target heterodimers and their corresponding monomers was performed both through oxidative amination reactions assisted by ultrasound and CeCl3·7H2O catalysis "in water". This eco-friendly procedure was successfully extended to the one-pot synthesis of homodimers derived from the 7-phenylaminoisoquinolinequinone pharmacophore. The electrochemical properties of the monomers and dimers were determined by cyclic and square wave voltammetry. The number of electrons transferred during the oxidation process, associated to the redox potential EI1/2, was determined by controlled potential coulometry.

Preparation of Novel Homodimers Derived from Cytotoxic Isoquinolinequinones. A Twin Drug Approach.

The synthesis of five novel homodimers is reported based on the anilinoisoquinolinequinone scaffold. In these twin-drug derivatives, two units of the anilinoquinone pharmacophores are linked through a methylene spacer. The formation of dimers was achieved by reaction of isoquinolinequinones with 4, 4'-diaminodiphenylmethane via a sequence of two oxidative amination reactions. A preliminary in vitro screening of the homodimers reveals moderate to high cytotoxic activities against MDA-MB-21 breast adenocarcinoma and B16-F10 murine metastatic melanoma cell lines. The asymmetrical homodimer 15 stands out due to its cytotoxic potencies at submicromolar concentrations and high selectivity index (mean IC50 = 0.37 µM; SI = 6.97) compared to those of etoposide (mean IC50 = 3.67; SI = 0.32) and taxol (mean IC50 = 0.35; SI = 0.91) employed as reference anticancer drugs.