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Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer’s disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates. Given the reciprocal relationship of the increasing burden of human diseases and limited availability of medicinal therapies, more rapid drug discovery and development are desirable. To expedite clinically relevant drug development, we present here evidence on bioactive compounds from the genera Allium, Tulgbaghia, Cyrtanthus and Crinum and describe their traditional and pharmacological applications.

Despite the success of combination antiretroviral therapy (cART), HIV persists in low- and middle-income countries (LMIC) due to emerging drug resistance and insufficient drug accessibility. Furthermore, cART does not target latently-infected CD4+ T cells, which represent a major barrier to HIV eradication. The “shock and kill” therapeutic approach aims to reactivate provirus expression in latently-infected cells in the presence of cART and target virus-expressing cells for elimination. An attractive therapeutic prototype in LMICs would therefore be capable of simultaneously inhibiting viral replication and inducing latency reversal. Here we report that Gnidia sericocephala, which is used by traditional health practitioners in South Africa for HIV/AIDS management to supplement cART, contains at least four daphnane-type compounds (yuanhuacine A (1), yuanhuacine as part of a mixture (2), yuanhuajine (3), and gniditrin (4)) that inhibit viral replication and/or reverse HIV latency. For example, 1 and 2 inhibit HIV replication in peripheral blood mononuclear cells (PBMC) by >80% at 0.08 µg/mL, while 1 further inhibits a subtype C virus in PBMC with a half-maximal effective concentration (EC50) of 0.03 µM without cytotoxicity. Both 1 and 2 also reverse HIV latency in vitro consistent with protein kinase C activation but at 16.7-fold lower concentrations than the control prostratin. Both 1 and 2 also reverse latency in primary CD4+ T cells from cART-suppressed donors with HIV similar to prostratin but at 6.7-fold lower concentrations. These results highlight G. sericocephala and components 1 and 2 as anti-HIV agents for improving cART efficacy and supporting HIV cure efforts in resource-limited regions.

Elevated levels of the amylo β-proteins (Aβ), particularly Aβ42, are associated with a high risk of Alzheimer’s disease (AD). The Aβ proteins are produced from cellular processing of the amyloid precursor proteins (APPs). To identify natural products that block the formation of Aβ-proteins from APPs, we previously screened a library of plant extracts and identified Xysmalobium undulaum (Apocynaceae) as a potential plant for further research. Here, we provide a report on the isolation and identification of the active principles from the plant species using a bioassay-guided fractionation. Fractions and resulting pure compounds from the purification process of the extract of X. undulatum were screened in vitro against APPs transfected HeLa cell lines. Three compounds, acetylated glycosydated crotoxogenin (1), xysmalogenin-3, β-d-glucopyranoside (2), and crotoxigenin 3-O-glucopyranoside (3), were subsequently isolated and their structures elucidated using NMR and mass spectrometry. Compound 1, a novel cardenolide, and 2 significantly decreased the Aβ42 levels in a dose-dependent manner while compound 3 was inactive. In silico investigations identified the AD’s β-secretase enzyme, BACE1, as a potential target for these compounds with the glycoside moiety being of significance in binding to the enzyme active site. Our study provides the first report of a novel cardenolide and the potential of cardenolides as chemical scaffolds for developing AD treatment drugs.

The ability to block human-to-mosquito and mosquito-to-human transmission of Plasmodium parasites is fundamental to accomplish the ambitious goal of malaria elimination. The WHO currently recommends only primaquine as a transmission-blocking drug but its use is severely restricted by toxicity in some populations. New, safe and clinically effective transmission-blocking drugs therefore need to be discovered. While natural products have been extensively investigated for the development of chemotherapeutic antimalarial agents, their potential use as transmission-blocking drugs is comparatively poorly explored. Here, we provide a comprehensive summary of the activities of natural products (and their derivatives) of plant and microbial origins against sexual stages of Plasmodium parasites and the Anopheles mosquito vector. We identify the prevailing challenges and opportunities and suggest how these can be mitigated and/or exploited in an endeavor to expedite transmission-blocking drug discovery efforts from natural products.