Synthesis, in vitro Antileishmanial Efficacy and Hit/Lead Identification of Nitrofurantoin‐Triazole Hybrids

Abstract

Leishmaniasis is a vector-borne neglected parasitic infection affecting thousands of individuals, mostly among populations in low-to moderate-income developing countries. In the absence of protective vaccines, the management of the disease banks solely on chemotherapy. However, the clinical usefulness of current antileishmanial drugs is threatened by their toxicity and the emergence of multidrug-resistant strains of the causative pathogens. This emphasizes the imperative for the development of new and effective antileishmanial agents. In this regard, we synthesized and evaluated in vitro the antileishmanial activity and cytotoxicity profile of a series of nitrofurantoin-triazole hybrids. The nitrofurantoin derivative 1 featuring propargyl moiety was distinctively the most active of all, was nontoxic to human cells and possessed submicromolar cellular activity selectively directed towards the pathogens of the life threatening visceral leishmaniasis. Hence it was identified as potential antileishmanial lead for further investigation into its prospective to act as alternative to therapies.

Exploration of ethylene glycol linked nitrofurantoin derivatives against Leishmania: Synthesis and in vitro activity

“…All the synthesised compounds had very poor growth inhibition against the amastigote form of both strains, indicating that these analogues were not cidal in nature; however, they may potentially have static antileishmanial activity. Previously, Zuma et al [ 25 ] screened compound 4 (analogue 2n in this study) for antileishmanial activity. A modified method of Njanpa et al [ 39 ] was used, which is similar to the assay of Jain et al [ 38 ] except the plates were incubated for only 24 h after macrophage lysis to measure amastigote viability instead of amastigote recovery and transformation.…”

“…Future work on ethylene glycol derivatives of NFT will focus on the investigation of novel analogues with improved physicochemical properties with the aim to achieve higher cellular permeability and potential enhanced anti-amastigote activity in the search for new antileishmanial agents. a NFT data as reported by Zuma et al [25] 4 | EXPERIMENTAL 4.1 | Chemistry…”

“…However, these hits appeared insoluble in the in vivo testing media which resulted in poor to no activity in the mice study. [ 24 ] Zuma et al, [ 25 ] conducted another study wherein the antileishmanial activity of novel NFT‐triazole hybrids was assessed against the second major species of the kinetoplastidae family, that is, Leishmania , which is taxonomic to Trypanosoma . Propargyl intermediary analogue 3 and hydrid 4 (Figure 2) were identified as in vitro antileishmanial leads combining with good safety and activity profiles.…”

Probing benzothiadiazine-1,1-dioxide ethylene glycol derivatives against Leishmania: synthesis and in vitro efficacy evaluation

“…In this study, terminal alkyl/aryl substituents as well as chain length of the ethylene oxide, were considered to assess potential structure-activity relationship (SAR), if any, in the series. Furthermore, a propargyl moiety was also investigated to evaluate its impact on biological activity, seeing that it had previously shown to greatly boost the antileishmanial e cacy of nitrofurantoin [23]. The general structure of the target compounds is depicted in Fig.…”

Antiproliferative Activity and Ultrastructural Changes in Promastigote and Amastigote forms of Leishmania amazonensis Caused by Limonene‐Acylthiosemicarbazide Hybrids

“…It is estimated that around one billion people are affected or exposed to the agents that cause these diseases. The NTDs mainly affect the most socially and economically challenged populations in low‐income countries, being associated with malnutrition, poor housing conditions, population displacement and lack of resources [1–4] . Among them, leishmaniasis, a zoonotic and endemic disease, is found in 98 countries around the world, being present in Europe, Africa, the Americas, Asia, and Australia [5,6] .…”