Synthesis and biological activity of novel bisquinazolinone derivatives

Abstract

Leishmaniasis is a vector-borne disease caused by the Leishmania parasite. Although there are 20 species that can infect humans, L. donovani is responsible for the majority of visceral leishmaniasis and L. major is responsible for the majority of cutaneous leishmaniasis. In 2019, the estimated annual number of leishmaniasis cases ranged from 700 000 to 1 million, with a death count of 26 000 to 65 000. Chemotherapy, which is the most effective control strategy for leishmaniasis, is structured around five drugs, namely pentavalent antimonials, amphotericin B, paromomycin, pentamidine and miltefosine. However, these drugs possess undesirable characteristics including toxicity, impractical and inaccessible administration (intramuscular (IM) or intravenous (IV) injections) with the exception of miltefosine; which discourages patient compliance and contributes to the emergence of drug resistant leishmanial parasites. Furthermore, leishmaniasis is a neglected disease with growing area distribution. Consequently, the search for new functional, safe and affordable antileishmanial agents is thus urgent and essential. In this study, an investigation of febrifugine and bisquinazolinone derivatives as antileishmanial agents was undertaken. Quinazolinones, such as febrifugine possess excellent antiprotozoal activity, which includes antileishmanial activity. Shortcomings such as unfavourable toxicity profiles and structural hindrances, chiral centres causing isomer formation, limit their potential as chemotherapeutic agents. Additionally, although these agents occur in nature, derivatisation is often lengthy and provides poor yields. Therefore, in this study two series of compounds (febrifugine derivatives and bisquinazolinone derivatives) were synthesised in a maximum of three steps (condensation, acylation and nucleophilic substitution) and targeting N-3 as the site of reaction. Target compounds were synthesised by Sᴎ2 nucleophilic substitution and isolated by recrystallisation and column chromatography in poor to average yields. After chemical analysis and structure confirmation, the derivatives were prepared for antileishmanial screening against L. donovani and L. major promastigotes. synthesised derivatives had poor activity (growth inhibition <30%) against the Leishmania strains. However, it was noted that the febrifugine derivatives were more potent against L. major (growth inhibition 0 − 35%), while the bisquinazolinone derivatives were more potent against L. donovani (growth inhibition 0 − 30%). Furthermore, cytotoxicity of the derivatives was assessed against mammalian (Vero) cells. The compounds had excellent toxicity profiles (IC₅₀ >100 µM). Although the antileishmanial activity of the derivatives was inadequate when compared to clinical drugs, the lack of cytotoxicity may be a good starting point for the future development of these agents. Through improved design and modification, these derivatives could be building-blocks for future projects.