Original Computational and Experimental Investigation of Novel Nitrogen-Containing Heterocyclic Compounds as Dual Antimalarial and Antibacterial Agents

The global burden of antimicrobial resistance and malaria, both of which are deeply intertwined with Nigerian public health challenges, creates an urgent need for novel pharmacological entities with dual-activity profiles that can address co-infections and simplify treatment regimens. Nitrogen-containing heterocyclic scaffolds, particularly quinoline, benzimidazole, and triazole derivatives, constitute privileged medicinal chemistry platforms with demonstrated activity against multiple pathogens. This study designed, synthesised, and evaluated a series of novel nitrogen-containing heterocyclic compounds as dual antimalarial and antibacterial agents using an integrated computational and experimental approach that constitutes an original methodological contribution. Pharmacophore modelling and molecular docking against Plasmodium falciparum dihydroorotate dehydrogenase and bacterial DNA gyrase B targets guided the rational design of thirty-two novel compounds. Synthesis employed multi-component reactions combining locally available feedstocks including furfural derived from Nigerian agricultural waste. All compounds were fully characterised by high-resolution mass spectrometry, one- and two-dimensional nuclear magnetic resonance, infrared spectroscopy, and elemental analysis. In vitro antimalarial activity was assessed against chloroquine-sensitive and resistant P. falciparum strains. Antibacterial activity was evaluated against multi-drug-resistant clinical isolates obtained from Nigerian university teaching hospitals. Twelve compounds showed antimalarial IC50 values below 500 nanomolar against both strains without cross-resistance to chloroquine. Eight of these also demonstrated minimum inhibitory concentrations below 4 micrograms per millilitre against methicillin-resistant Staphylococcus aureus. Pharmacokinetic parameters were predicted using ADMET Predictor software. This original chemotherapeutic scaffold represents a priority candidate for further preclinical development.

Keywords: heterocyclic compounds, dual activity, antimalarial, antibacterial, molecular docking