ABSTRACT
Carbon dioxide (CO2) is an economically viable and abundant carbon source that can be incorporated into compounds such as 1,3-azoles relevant to the pharmaceutical, cosmetics, and pesticide industries. Of the 2.4 million commercially available C2-unsubstituted 1,3-azole compounds, less than 1 % are currently purchasable as their C2-carboxylated derivatives, highlighting the substantial gap in compound availability. This availability gap leaves ample opportunities for exploring the synthetic accessibility and use of carboxylated azoles in bioactive compounds. In this study, we analyze and quantify the relevance of C2-carboxylated 1,3-azoles in small-molecule research. An analysis of molecular databases such as ZINC, ChEMBL, COSMOS, and DrugBank identified relevant C2-carboxylated 1,3-azoles as anticoagulant and aroma-giving compounds. Moreover, a pharmacophore analysis highlights promising pharmaceutical potential associated with C2-carboxylated 1,3-azoles, revealing the ATP-sensitive inward rectifier potassium channel 1 (KATP) and Kinesin-like protein KIF18A as targets that can potentially be addressed with C2-carboxylated 1,3-azoles. Moreover, we identified several bioisosteres of C2-carboxylated 1,3-azoles. In conclusion, further exploration of the chemical space of C2-carboxylated 1,3-azoles is encouraged to harness their full potential in drug discovery and related fields.
ABSTRACT
BACKGROUND: Nature has perennially served as an infinite reservoir of diverse chemicals with numerous applications benefiting humankind. In recent years, due to the emerging COVID-19 pandemic, there has been a surge in studies on repurposing natural products as anti-SARS-CoV-2 agents, including plant-derived substances. Among all types of natural products, alkaloids remain one of the most important groups with various known medicinal values. The current investigation focuses on Amaryllidaceae alkaloids (AAs) since AAs have drawn significant scientific attention as anti-SARS-CoV-2 agents over the past few years. PURPOSE AND STUDY DESIGN: This study serves as a mini-review, summarizing recent advances in studying the anti-SARS-CoV-2 potency of AAs, covering two aspects: structure-activity relationship and mechanism of action (MOA). METHODS: The study covers the period from 2019 to 2023. The information in this review were retrieved from common databases including Web of Science, ScienceDirect, PubMed and Google scholar. Reported anti-SARS-CoV-2 potency, cytotoxicity and possible biological targets of AAs were summarized and classified into different skeletal subclasses. Then, the structure-activity relationship (SAR) was explored, pinpointing the key pharmacophore-related structural moieties. To study the mechanism of action of anti-SARS-CoV-2 AAs, possible biological targets were discussed. RESULTS: In total, fourteen research articles about anti-SARS-CoV-2 was selected. From the SAR point of view, four skeletal subclasses of AAs (lycorine-, galanthamine-, crinine- and homolycorine-types) appear to be promising for further investigation as anti-SARS-CoV-2 agents despite experimental inconsistencies in determining in vitro half maximal inhibitory effective concentration (EC50). Narciclasine, haemanthamine- and montanine-type skeletons were cytotoxic and devoid of anti-SARS-CoV-2 activity. The lycorine-type scaffold was the most structurally diverse in this study and preliminary structure-activity relationships revealed the crucial role of ring C and substituents on rings A, C and D in its anti-SARS-CoV-2 activity. It also appears that two enantiomeric skeletons (haemanthamine- and crinine-types) displayed opposite activity/toxicity profiles regarding anti-SARS-CoV-2 activity. Pharmacophore-related moieties of the haemanthamine/crinine-type skeletons were the substituents on rings B, C and the dioxymethylene moiety. All galanthamine-type alkaloids in this study were devoid of cytotoxicity and it appears that varying substituents on rings C and D could enhance the anti-SARS-CoV-2 potency. Regarding MOAs, initial experimental results suggested Mpro and RdRp as possible viral targets. Dual functionality between anti-inflammatory activity on host cells and anti-SARS-CoV-2 activity on the SARS-CoV-2 virus of isoquinoline alkaloids, including AAs, were suggested as the possible MOAs to alleviate severe complications in COVID-19 patients. This dual functionality was proposed to be related to the p38 MAPK signaling pathway. CONCLUSION: Overall, Amaryllidaceae alkaloids appear to be promising for further investigation as anti-SARS-CoV-2 agents. The skeletal subclasses holding the premise for further investigation are lycorine-, crinine-, galanthamine- and homolycorine-types.
