Leishmaniasis is a parasitic disease and is categorized as a tropically neglected disease (NTD) with no effective vaccines available. The available chemotherapeutics against leishmaniasis are associated with an increase in the incidence of toxicity and drug resistance. Consequently, targeting metabolic pathways and enzymes of parasites which differs from the mammalian host can be exploited to treat and overcome the resistance. The classical methods of identifying the structural fragments and the moieties responsible for the biological activities from the standard compounds and their modification are options for developing more effective novel compounds. Significant progress has been made in refining the development of potent non-toxic molecules and addressing the limitations of the current treatment available. Several examples of synthetic product-based approach utilizing their core heterocyclic rings including furan, pyrrole, thiazole, imidazole, pyrazole, triazole, quinazoline, quinoline, pyrimidine, coumarin, indole, acridine, oxadiazole, purine, chalcone, carboline, phenanthrene and metal containing derivatives and their structure-activity relationships are discussed in this review. It also analyses the groups/fragments interacting with the host cell receptors and will support the medicinal chemists with novel antileishmanial agents.