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.

Melicoccus bijugatus (Guinep) is traditionally consumed in the Caribbean and Latin America for its health benefits, yet its cardiovascular effects remain underexplored. This study investigated the therapeutic potential of Guinep by combining experimental and computational approaches. The biological evaluation of the Guinep extract was conducted by assessing the effects of modulating Angiotensin-Converting Enzyme (ACE), Angiotensin II Type 1 Receptor (AT1R), and Voltage-Gated Calcium Channels (VGCC) on vascular reactivity. Metabolites previously identified by high-resolution UHPLC-Q-Orbitrap mass spectrometry were further examined using in silico tools, including ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) prediction (pkCSM), biological activity prediction (PASS server), and molecular docking (AutoDock Vina) against cardiovascular targets (ACE: PDB 1O86, AT1R: PDB 4ZUD, VGCC: PDB 8WE8). Docking results revealed that phytochemicals such as isorhamnetin-3-O-glucoside and 3-O-caffeoylquinic acid displayed strong binding affinities with ACE (−9.3 and −8.5 kcal/mol), AT1R (−8.2 and −7.6 kcal/mol), and VGCC (−8.6 and −7.6 kcal/mol), in several cases matching or surpassing standard antihypertensive drugs. Key hydrogen bond interactions closely resembled those of reference ligands, suggesting pharmacophoric similarity. ADMET modeling confirmed favorable pharmacokinetic profiles and low predicted toxicity, supporting their drug-like potential. These findings are consistent with in vivo evidence of Guinep’s hypotensive, antioxidant, and vasodilatory properties. Vascular relaxation of Guinep extract was predominantly mediated by blockade of VGCC (53%) and AT1R (48%), while ACE inhibition accounted for 24%. Collectively, the results demonstrate that Guinep contains bioactive phytochemicals with multitarget cardiovascular activity, particularly as ACE, AT1R, and VGCC modulators. This study validates the traditional use of Guinep.

Background/Objectives: Paracetamol is a widely analgesic and antipyretic drug; however, its limited anti-inflammatory efficacy and safety concerns motivate the search for novel non-opioid alternatives. In this study, a series of 4-hydroxyphenylamino-naphthoquinones were designed as paracetamol-inspired analogs and synthesized via a solvent-free, silica-assisted Michael addition, providing a sustainable and efficient synthetic route. Methods: The compounds were evaluated using an integrated strategy combining in silico prediction, density functional theory calculations, molecular docking, ADMET profiling, and in vivo phenotypic pharmacological assays. Results: In vivo evaluation revealed pronounced peripheral antinociceptive activity in the acetic acid-induced writhing model and robust anti-inflammatory effects in carrageenan-induced paw edema, comparable to those of naproxen. These findings suggest a predominantly peripheral mechanism consistent with anti-inflammatory and antinociceptive profiles linked to cyclooxygenase inhibition. A normalization-based multi-criteria analysis integrating peripheral, anti-inflammatory, central, and antipyretic endpoints enabled transparent phenotypic prioritization within the series. Under this framework, compound 7 emerged as the most balanced peripheral–anti-inflammatory candidate, whereas compound 8, evaluated experimentally as a regioisomeric mixture, showed comparatively stronger central antinociceptive activity in the hot plate test. Antipyretic activity in an LPS-induced fever model was limited and not sustained. Conclusions: Overall, these findings indicated that the 4-hydroxyphenylamino-naphthoquinone scaffold emerges as a promising non-opioid platform for peripheral inflammatory pain, supporting further investigation of its pharmacological and mechanistic properties.