| dc.description.abstract | Leishmaniasis is a disease resulting from the ingress of protozoan protists of the genus Leishmania (L.) into the mononuclear phagocytes of vertebrate hosts. These parasites are mainly transmitted by the haematophagous activities of female phlebotomine sand flies in the genera Phlebotomus (Old World) and Lutzomyia (New World). Leishmaniasis is traditionally classified into three clinical forms, namely: visceral leishmaniasis (a febrile chronic infection associated with hepatosplenomegaly and cytopenias), cutaneous leishmaniasis (associated with chronic, slow-healing skin lesions and ulcers) and mucosal/mucocutaneous leishmaniasis (an oligoparasitic form of the disease characterised by ulceration and destruction of the mucosa of the nose, pharynx, larynx and mouth). The life cycle of Leishmania parasites alternates between two main morphological forms. These are the promastigote (an elongated, motile and flagellated form of the parasite found in the digestive tract and proboscis of sand flies) and amastigote forms (a rounded, non-motile and non-flagellated form of the parasite that usually infects the mononuclear phagocytes of vertebrate hosts). Leishmaniasis is endemic to over 98 countries, where an estimated 1 billion people are at risk of contracting the disease. Approximately 12 million individuals are estimated to be infected at any single point in time. The exact number of new cases per year is not known with certainty. The World Health Organisation (2020) estimates that around 600,000 - 1 million new cases of cutaneous leishmaniasis, and some 50,000 - 90,000 new cases of visceral leishmaniasis, occur annually. Visceral leishmaniasis is also estimated to be directly responsible for causing over 20,000 - 40,000 deaths every year. Unfortunately, there is no single preventative, commercial vaccine or chemoprophylaxis available for use in humans. Presently, there are only a limited number of drugs available for the treatment of leishmaniasis. These include the pentavalent antimonials (sodium stibogluconate and meglumine antimoniate), amphotericin B, miltefosine, pentamidine and paromomycin - all of whom have limitations in terms of their efficacy, toxicity, cost, route of administration, frequency of administration and duration of treatment. The treatment of leishmaniasis is also complicated by the occurrence of treatment failure and the development of drug resistance in parasites. All of the above serves to underscore the urgent need to develop novel anti-leishmanial agents. In view of this need, a series of fourteen 4(3H)-quinazolinone derivatives, comprising ten 1H-1,2,3-triazole-4(3H)-quinazolinone hybrids and their synthetic precursors, were synthesised in low to excellent yields (30 - 89%) using cyclisation, condensation, nucleophilic (SN2) substitution and copper-catalysed alkyne-azide cycloaddition (CuAAC) reactions. The anti-leishmanial activity and cytotoxicity of these hybrids, and their associated synthetic intermediates, were duly investigated in the present study. The anti-leishmanial activities of the derivatives (expressed as percentage growth inhibition ± standard deviation (SD)) against the promastigotes of three strains of Leishmania parasite (L. donovani 1S and 9515, and L. major IR-173) were determined using a resazurin-based assay. Amphotericin B (AMB) served as the reference drug. The cytotoxicity (IC₅₀, or half-maximal concentration) of the derivatives against Vero cells (expressed as the mean (μM)± standard deviation (SD)) was also determined using a resazurin-based assay, with emetine (EM) as the reference drug. All 4(3H)-quinazolinone derivatives were established to be sparingly soluble in the screening medium and were tested as suspensions. All synthesised derivatives and reference drugs were screened at single-point concentrations of 100 μM. All derivatives in this study were found to be non-toxic to Vero cells (IC₅₀ > . Two derivatives were found to possess moderate anti-leishmanial activity. These were compounds 2a (58% and 43% growth inhibition of L. donovani 1S and 9515 promastigotes, respectively) and 4b (48% growth inhibition of L. major IR-173 promastigotes). Compound 2a is characterised by the inclusion of a propargyl group substituted at position 3 of its 4(3H)-quinazolinone scaffold, while compound 4b has a brominated 1H-1,2,3-triazole-containing moiety substituted in this position. Both compounds contain a styryl moiety substituted at position 2 of their respective 4(3H)-quinazolinone scaffolds. The lack of significant anti-leishmanial activity of the synthesised derivatives may be attributed to their poor solubility in the aqueous screening medium, the remediation of which may be relegated to future studies. | |
