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Browsing Theses and Dissertations by Author "Andayi, W. A."
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Item Open Access Design, Synthesis, And Biological Evaluation of Anti-HIV and Anti-plasmodial Activities of Some Hydroxypyridinone-aminoquinoline Derivatives(2025-09-05) Munapo, Tinotenda Deoleen; Bvumbi, M. V.; Andayi, W. A.Malaria and HIV-AIDS are fatal infectious diseases. Given the overlap of their geographic distribution and resultant coinfection rates, interactions between the two diseases pose major public health problems are the most vulnerable population groups. Young children and pregnant women are the most vulnerable population groups, yet they have limited medication options because of immunocompromising. The levels of CYP3A4 in children and pregnant women is elevated and thus necessitating dose adjustments for most drugs in clinical use to achieve treatment success. Without the dose adjustment the resultant low drug bioavailability exposes pathogens to sub-optimal dosages thus fomenting drug resistance. Hydroxypyridinone-aminoquinoline (HPO-AQS) compounds which were found to be potent CYP3A4 inhibitors, could be repurposed as antimalarials and anti-HIV specifically for children and expectant mothers. Thus, the study also aims at repurposing HPO-AQS for treatment of HIV-AIDS and malaria coinfections. Despite the CYP3A4 liability of the HPO-AQs, these molecules can be repurposed for chemotherapeutic applications in cancer and HIV-AIDS where CYP3A4 inhibition is not an issue if risk and benefit analysis is carefully considered. The rational design was based on quinoline as an antimalarial pharmacophore and iron chelation inhibition of plasmodium proliferation in addition to studies earlier done by Andayi et al. The HPO-AQS were designed in two series (kojic derivatives and maltol derivatives) in such a way that they have a chelator (HPO) linked to quinoline nucleus with varying linker lengths. Thereafter, the in-silico predictions were done using SwissADME. The attention of this work was focused on the predictions of lipophilicity, physicochemical properties, and CYP isoform targets. SwissADME results predicted that HPO-AQs could be developed as synthetic medical products. This has been the basis of subsequent synthesis and in vitro studies. The kojic derived compounds (1a-l) were prepared by coupling N-(7-chloro-4-quinolinyl)-diaminoalkanes (6a-g) to 2-(chloromethyl)-5 (benzyloxy)-1-alkylpyridin-4-(1H)-ones (3a-3c). The synthesis of the maltol-derived (2a-i) conjugates involved the Michael addition of N-(7-chloro-4- quinolinyl)-diaminoalkanes (6a-g) to 3-benzyl protected methyl maltol (10a) or protected ethyl maltol (10b). Nuclear magnetic resonance spectroscopy and Mass Spectroscopy confirmed the successful synthesis of all the target compounds. The target compounds were evaluated for their cytotoxicities, anti-HIV, antiplasmodial, anticancer and antioxidant activities in vitro. A general observation on the toxicities of all the compounds, when evaluated on three different cell lines, is that maltol-derived compounds (2b and 2d) were more toxic compared to the kojic-derived compounds (1a, 1b, 1f and 1g). With this observation, the kojic moiety counteracts the toxic effects caused by the quinoline scaffold better than the maltol moiety. Based on the TZM-bI cells MTT assays, the most nontoxic compounds [1b; 1e; 1f; 1g and 2b] with relatively higher IC50 values, were further evaluated for anti-HIV (Reverse Transcription Inhibition and HIV Protease Activity inhibition) and antioxidant activities. The compounds with lower cytotoxicity IC50 values in the TZM bl cell line [1a and 2d] were further evaluated for their anti-cancer properties using the Nitric Oxide Assays. In the reverse transcriptase assays, 1e (IC50 = 26.2±0.19μM) and 1f (IC50 = 32.90±3.79μM) were the better inhibitors whilst 1g (IC50 = 56.56 ± 0.74μM) was the least inhibitor. In the protease inhibition assay, 1e was the best inhibitor (in relation to the positive control). Of the two evaluated compounds, 1a and 2d, none of them produced nitric oxide as expected, as the tested compounds were not very toxic but moderately toxic in the cytotoxic assays, as observed by the cytotoxicity results. The protected HPO-AQS showed no antioxidative potential, and 1b only showed antioxidant properties but only in high concentrations. The antiplasmodial activities of HPO-AQS were evaluated against the chloroquine drug-sensitive (NF54) and the chloroquine drug-resistant strains (K1). These activities on the wild-type isolate, P. falciparum Nf54, range from moderate to very high, with some IC50 values below 20nM, which is comparable to the control antimalarial agents. Resistance indices analysis showed that most of the compounds had values greater than 5, except for 1a with RI = 3.5. However, there is cross-resistance for the rest of the compounds, which can be expected of these compounds due to their 7-chloroquinoline moiety.