Review on benzothiazole as a privileged nucleus for Plasmodium DHFR inhibition with structure guided comprehensive analysis
Malaria continues to be a major global health concern as Plasmodium falciparum became resistant to current drugs that target dihydrofolate reductase (DHFR). New scaffolds that are effective against resistant DHFR mutations are urgently needed. Artemisinin-based combination therapies (ACTs), the current first line treatment, are increasingly compromised by partial resistance, while widespread resistance to previous drugs such as chloroquine and antifolates further limits therapeutic options. Dihydrofolate reductase is a validated and essential enzyme in the parasite’s folate biosynthesis pathways, responsible for tetrahydrofolate production that is required for nucleotide synthesis. Recent structural and medicinal chemistry efforts have led to the development of flexible next-generation antifolates, including WR99210 and P128, which enhances inhibitory potency against mutant DHFR variants. This review reports 2-amino benzothiazole derivatives as a promising class of antimalarial agents with a distinct mechanism of action and highlights about in vitro antimalarial studies, synthetic approaches, structural activity relationships (SAR) and binding interactions of 2-amino benzothiazole derivatives.