Synthesis of Novel Antimalarial and Antitubercular Isonicotinohydrazides

Abstract

Malaria and tuberculosis (TB) though curable and preventable, remain serious public health problems globally, with devastating consequences. Co-infection of these two deadly diseases worsens the situation and particularly makes treatment very difficult. While the current mainstay for malaria treatment, artemisinins, may gradually lose their potency due to the development of resistance by P. falciparum, M. tuberculosis has developed Multi-Drug Resistance (MDR) and Extensive Drug Resistance (XDR) to current anti-TB drugs, due to patient incompliance resulting from long treatment regimen. This project focused on the synthesis of isonicotinohydrazides with the concept of molecular hybridisation, by incorporating 1,2,4,5- tetraoxane and hydrazine moieties to yield a single molecule that will exhibit both antimalarial and antitubercular activites. In all, ten novel hybrid molecules were designed, synthesised and characterised using FTIR, 1H and 13C NMR spectroscopy. All the compounds returned acceptable physicochemical parameters as well as good antimalarial activities against 3D7 strain of P. falciparum. In vitro IC50 values ranging from 0.060 ± 0.033 - 0.491 ± 0.012 μM were obtained. Five of the hybrid molecules tested against H37rv and M. aurum strains of Mtb using Microplate Alamar Blue Assay (MABA), gave satisfactory results while four of the compounds 101, 102, 103, 104, exhibited very good activity against H37rv with MIC values between 0.003-0.5 mg/mL, and M. aurum was resistant to all five tested compounds.