Spirocyclic chromanes exhibit antiplasmodial activities and inhibit all intraerythrocytic life cycle stages

Roberts, Bracken F.; Iyamu, Iredia D.; Lee, Sukjun; Lee, Eun-Young; Ayong, Lawrence; Kyle, Dennis E.; Yuan, Yu; Manetsch, Roman; Chakrabarti, Debopam

doi:10.1016/j.ijpddr.2016.02.004

Cited by 18 publications

(17 citation statements)

References 38 publications

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“…Stage Specific Activity Assay (SSA): The SSA was performed as described previously [ 34 ]. Briefly, P. falciparum Dd2 cultures were tightly synchronized by magnetic isolation of schizonts using MACS (Miltenyi Biotec, Auburn, CA, USA) column [ 35 ] followed by 5% sorbitol ( w/v ) treatment [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

Antiplasmodial Compounds from Deep-Water Marine Invertebrates

et al. 2021

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Novel drug leads for malaria therapy are urgently needed because of the widespread emergence of resistance to all available drugs. Screening of the Harbor Branch enriched fraction library against the Plasmodium falciparum chloroquine-resistant strain (Dd2) followed by bioassay-guided fractionation led to the identification of two potent antiplasmodials; a novel diterpene designated as bebrycin A (1) and the known C21 degraded terpene nitenin (2). A SYBR Green I assay was used to establish a Dd2 EC50 of 1.08 ± 0.21 and 0.29 ± 0.02 µM for bebrycin A and nitenin, respectively. Further analysis was then performed to assess the stage specificity of the inhibitors antiplasmodial effects on the Dd2 intraerythrocytic life cycle. Exposure to bebrycin A was found to block parasite maturation at the schizont stage if added any time prior to late schizogony at 42 hours post invasion, (HPI). In contrast, early life cycle exposure to nitenin (prior to 18 HPI) was identified as crucial to parasite inhibition, suggesting nitenin may target the maturation of the parasite during the transition from ring to early trophozoite (6–18 HPI), a novel property among known antimalarials.

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Section: Methodsmentioning

confidence: 99%

Antiplasmodial Compounds from Deep-Water Marine Invertebrates

et al. 2021

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“…The effect of UCF 501 on merozoite egress and invasion was also analyzed by an image-based assay described previously ( Roberts et al., 2016 ). Briefly, synchronized P. falciparum HB3 (chloroquine-sensitive) at 1.5% hematocrit and 5% parasitemia was exposed to each of N-acetylglucosamine (GlcNAc), E-64, artemisinin and UCF 501 at 10 μM final concentration for 24 h. The culture was than stained with wheat germ agglutinin-Alexa Fluor 488 conjugate and Mitotracker Red CMXRos each at 1 nM final concentrations, and incubated at 37 °C for 20 min.…”

Section: Methodsmentioning

confidence: 99%

4-Nitro styrylquinoline is an antimalarial inhibiting multiple stages of Plasmodium falciparum asexual life cycle

Roberts

Zheng

Cleaveleand

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Drugs against malaria are losing their effectiveness because of emerging drug resistance. This underscores the need for novel therapeutic options for malaria with mechanism of actions distinct from current antimalarials. To identify novel pharmacophores against malaria we have screened compounds containing structural features of natural products that are pharmacologically relevant. This screening has identified a 4-nitro styrylquinoline (SQ) compound with submicromolar antiplasmodial activity and excellent selectivity. SQ exhibits a cellular action distinct from current antimalarials, acting early on malaria parasite's intraerythrocytic life cycle including merozoite invasion. The compound is a fast-acting parasitocidal agent and also exhibits curative property in the rodent malaria model when administered orally. In this report, we describe the synthesis, preliminary structure-function analysis, and the parasite developmental stage specific action of the SQ scaffold.

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“…Stage-Specific Activity Assay P. falciparum Dd2 cell line was synchronized using a combination of 5% sorbitol and magnetic column separation as described (Roberts et al, 2016). Cultures at 2% parasitemia and 2% hematocrit were added to microtiter plate wells and measurements began 6 h post-invasion (6 hpi).…”

Section: Cytotoxicity Determinationmentioning

confidence: 99%

“…Pf Dd2 culture was synchronized as described (Roberts et al, 2016), plated into 24 well plates at 2% parasitemia and 2% hematocrit at 6 hpi. Compounds were added at 6, 18, or 30 hpi with a final concentration of 5X EC 50 .…”

Section: Rate Of Killing Determinationmentioning

confidence: 99%

DeepMalaria: Artificial Intelligence Driven Discovery of Potent Antiplasmodials

et al. 2020

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Antimalarial drugs are becoming less effective due to the emergence of drug resistance. Resistance has been reported for all available malaria drugs, including artemisinin, thus creating a perpetual need for alternative drug candidates. The traditional drug discovery approach of high throughput screening (HTS) of large compound libraries for identification of new drug leads is time-consuming and resource intensive. While virtual in silico screening is a solution to this problem, however, the generalization of the models is not ideal. Artificial intelligence (AI), utilizing either structure-based or ligand-based approaches, has demonstrated highly accurate performances in the field of chemical property prediction. Leveraging the existing data, AI would be a suitable alternative to blind-search HTS or fingerprint-based virtual screening. The AI model would learn patterns within the data and help to search for hit compounds efficiently. In this work, we introduce DeepMalaria, a deeplearning based process capable of predicting the anti-Plasmodium falciparum inhibitory properties of compounds using their SMILES. A graph-based model is trained on 13,446 publicly available antiplasmodial hit compounds from GlaxoSmithKline (GSK) dataset that are currently being used to find novel drug candidates for malaria. We validated this model by predicting hit compounds from a macrocyclic compound library and already approved drugs that are used for repurposing. We have chosen macrocyclic compounds as these ligandbinding structures are underexplored in malaria drug discovery. The in silico pipeline for this process also consists of additional validation of an in-house independent dataset consisting mostly of natural product compounds. Transfer learning from a large dataset was leveraged to improve the performance of the deep learning model. To validate the DeepMalaria generated hits, we used a commonly used SYBR Green I fluorescence assay based phenotypic screening. DeepMalaria was able to detect all the compounds with nanomolar activity and 87.5% of the compounds with greater than 50% inhibition. Further experiments to reveal the compounds' mechanism of action have shown that not only does one of the hit compounds, DC-9237, inhibits all asexual stages of Plasmodium falciparum, but is a fast-acting compound which makes it a strong candidate for further optimization.

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Spirocyclic chromanes exhibit antiplasmodial activities and inhibit all intraerythrocytic life cycle stages

Cited by 18 publications

References 38 publications

Antiplasmodial Compounds from Deep-Water Marine Invertebrates

Antiplasmodial Compounds from Deep-Water Marine Invertebrates

4-Nitro styrylquinoline is an antimalarial inhibiting multiple stages of Plasmodium falciparum asexual life cycle

DeepMalaria: Artificial Intelligence Driven Discovery of Potent Antiplasmodials

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