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DETERMINATION OF SELECTIVITY AND POTENTIAL FOR DRUG RESISTANCE OF NOVEL ANTIMALARIAL COMPOUNDS FROM NATURE-INSPIRED SYNTHETIC LIBRARIES
Title
DETERMINATION OF SELECTIVITY AND POTENTIAL FOR DRUG RESISTANCE OF NOVEL ANTIMALARIAL COMPOUNDS FROM NATURE-INSPIRED SYNTHETIC LIBRARIES.
Creator
Keasler, Eric, Keasler, Eric, University of Central Florida
Abstract / Description
As malaria, caused by Plasmodium spp., continues to afflict millions of people worldwide, there is a dire need for the discovery of novel, inexpensive antimalarial drugs. Although there are effective drugs on the market, the consistent development of drug resistant species has decreased their efficacy, further emphasizing that novel therapeutic measures are urgently needed. Natural products provide the most diverse reservoir for the discovery of unique chemical scaffolds with the potential to...
Show moreAs malaria, caused by Plasmodium spp., continues to afflict millions of people worldwide, there is a dire need for the discovery of novel, inexpensive antimalarial drugs. Although there are effective drugs on the market, the consistent development of drug resistant species has decreased their efficacy, further emphasizing that novel therapeutic measures are urgently needed. Natural products provide the most diverse reservoir for the discovery of unique chemical scaffolds with the potential to effectively combat malarial infections, but, due to their complex structures, they often pose extreme challenges to medicinal chemists during pharmacokinetic optimization. In our laboratory we have performed unbiased, cell-based assays of numerous synthetic compounds from chemical libraries enriched with nature-like elements. This screening has led to the discovery of many original chemical scaffolds with promising antimalarial properties. In an attempt to further characterize these scaffolds, the most promising compounds were assayed in order to determine their cytotoxic effects on mammalian cells. In addition, the development of a drug resistant parasite line of Plasmodium falciparum to the most promising compound was done in order to determine the relative probability for parasite resistance development.
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Date Issued
2012
Identifier
CFH0004223, ucf:44900
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH0004223
3-AMINO-2-PIPERIDINEQUINOLINE A NOVEL NATURAL PRODUCT-INSPIRED SYNTHETIC COMPOUND WITH ANTIMALARIAL ACTIVITY
Title
3-AMINO-2-PIPERIDINEQUINOLINE A NOVEL NATURAL PRODUCT-INSPIRED SYNTHETIC COMPOUND WITH ANTIMALARIAL ACTIVITY.
Creator
Valor, Cristhian, Chakrabarti, Debopam, University of Central Florida
Abstract / Description
Malaria afflicts about 500 million people worldwide thus causing significant global economic toll. The drugs available to treat the disease are rapidly losing their efficacy because of widespread prevalence of drug resistant parasites. Thus there is an urgent need to discover novel malaria therapeutics. This research is focused on to study the properties of a novel natural-like synthetic scaffold and analyze its selectivity, and cellular mechanism of action in Plasmodium falciparum. We have...
Show moreMalaria afflicts about 500 million people worldwide thus causing significant global economic toll. The drugs available to treat the disease are rapidly losing their efficacy because of widespread prevalence of drug resistant parasites. Thus there is an urgent need to discover novel malaria therapeutics. This research is focused on to study the properties of a novel natural-like synthetic scaffold and analyze its selectivity, and cellular mechanism of action in Plasmodium falciparum. We have identified a novel compound, 3-amino-2-piperidinequinoline (APQ), which we termed UCF401. APQ demonstrated IC50 at submicromolar concentrations against Plasmodium falciparum using the SYBR Green-I fluorescence assay measuring cellular proliferation. This compound also demonstrated low cytotoxicity against the NIH3T3 and HEPG2 cells using MTS assays, showing an IC50 of 174 uM and 125 uM respectively, suggesting of excellent selectivity. We evaluated the compliance of APQ with Lipinski's parameters and determined the in vitro physicochemical profiles of the compound. Our results show that APQ is a Lipinski parameter compliant and has good physicochemical properties. The cellular mechanism of action of APQ was characterized through the assessment of the effects of the compound at different stages of the parasite's intraerythrocytic life cycle. This assay was done by treating a synchronized cell line with the compound at 5X the IC50 value and then imaging the cells at 12-hour intervals. We found that APQ arrests parasite development at the trophozoite stage. In addition we determined that APQ is parasitocidal after a 96 h exposure. These results demonstrate that APQ can be considered as a validated hit and/or early lead.
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Date Issued
2014
Identifier
CFH0004593, ucf:45233
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH0004593
IDENTIFICATION OF NOVEL ANTIMALARIALS FROM MARINE NATURAL PRODUCTS FOR LEAD DISCOVERY
Title
IDENTIFICATION OF NOVEL ANTIMALARIALS FROM MARINE NATURAL PRODUCTS FOR LEAD DISCOVERY.
Creator
Alvarado, Stephenie, Chakrabarti, Debopam, University of Central Florida
Abstract / Description
An estimated 500 million cases of malaria occur each year. The increasing prevalence of drug resistant strains of Plasmodium in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for prophylaxis and treatment of this disease. Therefore, discovery of new, inexpensive, and effective drugs are urgently needed to combat this disease. Marine biodiversity is an enormous source of novel chemical entities and has been barely investigated for antimalarial...
Show moreAn estimated 500 million cases of malaria occur each year. The increasing prevalence of drug resistant strains of Plasmodium in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for prophylaxis and treatment of this disease. Therefore, discovery of new, inexpensive, and effective drugs are urgently needed to combat this disease. Marine biodiversity is an enormous source of novel chemical entities and has been barely investigated for antimalarial drug discovery. In an effort to discover novel therapeutics for malaria, we studied the antimalarial activities of a unique marine-derived peak fraction library provided by Harbor Branch Oceanographic Institute (HBOI). Within this unique library, we have screened 2,830 marine natural product (MNP) peak fractions through a medium throughput screening effort utilizing the SYBR Green-I fluorescence based assay, and have identified 253 fractions that exhibit antimalarial activity. From those inhibiting fractions we have identified twenty species of marine organisms that inhibit Plasmodium falciparum growth, from which thirty-five fractions were selected for further study. Among those thirty-five, eighty-three percent were also found to inhibit the chloroquine resistant strain of P. falciparum, Dd2. The most potent inhibitors were then screened for their cytotoxic properties using the MTT cell viability assay. Among the samples that exhibited potent inhibition of P. falciparum growth were fractions derived from a sponge of the genus Spongosorites sp.. This genus of sponge has been reported to contain the nortopsentin and topsentin class of bis-indole imidazole alkaloids. Nortopsentin A inhibited the parasite growth at the trophozoite stage with an IC50 value of 1.6 µM. This is the first report of antimalarial activity for this class of compound.
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Date Issued
2010
Identifier
CFE0003472, ucf:48932
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0003472
Discovery and characterization of antimalarial compounds with novel cellular mechanisms of action
Title
Discovery and characterization of antimalarial compounds with novel cellular mechanisms of action.
Creator
Roberts, Bracken, Chakrabarti, Debopam, Jewett, Travis, Self, William, University of Central Florida
Abstract / Description
Malaria kills over 500,000 people each year and over a third of the global population is at risk of infection. Though the human race has been fighting the malaria war for over 4,000 years and we have made great strides in eliminating malaria from many countries, we are treading on the edge of what could be another malaria epidemic primarily due to widespread drug resistance. There are documented cases of resistance for every known antimalarial in use today, including Artemisinins. It is...
Show moreMalaria kills over 500,000 people each year and over a third of the global population is at risk of infection. Though the human race has been fighting the malaria war for over 4,000 years and we have made great strides in eliminating malaria from many countries, we are treading on the edge of what could be another malaria epidemic primarily due to widespread drug resistance. There are documented cases of resistance for every known antimalarial in use today, including Artemisinins. It is critical that we open a new window of discovery in development of next generation antimalarials that circumvent current resistance paradigms. These compounds must attack new targets, have different speeds of action, and ideally possess powerful transmission blocking potential if they are to be successful antimalarial candidates. Screening endeavors historically focused on either synthetic or natural product libraries. Recent efforts have focused on combining privilege elements of natural products into synthetically tractable compounds to create hybrid libraries. To discover novel antimalarial pharmacophores, we have screened natural products derived from marine biodiversity as well as natural product-inspired synthetic libraries. Our phenotypic screening of 3,164 marine natural products from the Harbor Branch Oceanographic Institute, 56 high density combinatorial natural product based libraries from the Torrey Pines Institute for Molecular Studies, alkaloid, terpene, and macrocyclic libraries from Memorial Sloan Kettering Cancer Center, and 594 natural productinspired compounds from Asinex have identified several new selective antiplasmodial hit chemotypes. iv In this study, we have focused on compounds that exhibit cellular actions differing from current antimalarials. Two of the scaffolds, UCF 201 and 501, a spirocyclic chromane and a nitroquinoline, respectively, act early in the development cycle and block invasion. The alkaloid derived compound M03 blocks egress. UCF 501 cures malaria in the rodent model and significantly inhibits stage V gametocytogenesis. Given that discovery of transmission blocking agents are a priority in the malaria elimination strategies, this result is significant. This work is of high impact as it addresses a critical need in the field- next generation antimalarial scaffolds for malaria therapy and elimination campaign.
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Date Issued
2017
Identifier
CFE0006785, ucf:51815
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0006785
CHARACTERIZATION OF NOVEL ANTIMALARIALS FROM COMPOUNDS INSPIRED BY NATURAL PRODUCTS USING PRINCIPAL COMPONENT ANALYSIS (PCA)
Title
CHARACTERIZATION OF NOVEL ANTIMALARIALS FROM COMPOUNDS INSPIRED BY NATURAL PRODUCTS USING PRINCIPAL COMPONENT ANALYSIS (PCA).
Creator
Balde, Zarina Marie G, Chakrabarti, Debopam, University of Central Florida
Abstract / Description
Malaria is caused by a protozoan parasite, Plasmodium falciparum, which is responsible for over 500,000 deaths per year worldwide. Although malaria medicines are working well in many parts of the world, antimalarial drug resistance has emerged as one of the greatest challenges facing malaria control today. Since the malaria parasites are once again developing widespread resistance to antimalarial drugs, this can cause the spread of malaria to new areas and the re-emergence of malaria in areas...
Show moreMalaria is caused by a protozoan parasite, Plasmodium falciparum, which is responsible for over 500,000 deaths per year worldwide. Although malaria medicines are working well in many parts of the world, antimalarial drug resistance has emerged as one of the greatest challenges facing malaria control today. Since the malaria parasites are once again developing widespread resistance to antimalarial drugs, this can cause the spread of malaria to new areas and the re-emergence of malaria in areas where it had already been eradicated. Therefore, the discovery and characterization of novel antimalarials is extremely urgent. A previous drug screen in Dr. Chakrabarti's lab identified several natural products (NPs) with antiplasmodial activities. The focus of this study is to characterize the hit compounds using Principal Component Analysis (PCA) to determine structural uniqueness compared to known antimalarial drugs. This study will compare multiple libraries of different compounds, such as known drugs, kinase inhibitors, macrocycles, and top antimalarial hits discovered in our lab. Prioritizing the hit compounds by their chemical uniqueness will lessen the probability of future drug resistance. This is an important step in drug discovery as this will allow us to increase the interpretability of the datasets by creating new uncorrelated variables that will successively maximize variance. Characterization of the Natural Product inspired compounds will enable us to discover potent, selective, and novel antiplasmodial scaffolds that are unique in the 3-dimensional chemical space and will provide critical information that will serve as advanced starting points for the antimalarial drug discovery pipeline.
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Date Issued
2018
Identifier
CFH2000405, ucf:45893
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000405
IDENTIFICATION OF POTENTIAL LEAD ANTIMALARIAL COMPOUNDS FROM MARINE MICROBIAL EXTRACTS
Title
IDENTIFICATION OF POTENTIAL LEAD ANTIMALARIAL COMPOUNDS FROM MARINE MICROBIAL EXTRACTS.
Creator
Carbonell, Abigail, Chakrabarti, Debopam, University of Central Florida
Abstract / Description
Malaria, caused by the parasite Plasmodium falciparum, has a long history as a global health threat. The vector-borne disease causes millions of deaths yearly, especially in developing countries with tropical climates that facilitate transmission. Compounding the problem is the emergence of drug-resistant strains due to overuse of outdated treatments. New compounds with antiplasmodial activity are needed to be developed as effective drugs against malaria. The hypothesis for this project is...
Show moreMalaria, caused by the parasite Plasmodium falciparum, has a long history as a global health threat. The vector-borne disease causes millions of deaths yearly, especially in developing countries with tropical climates that facilitate transmission. Compounding the problem is the emergence of drug-resistant strains due to overuse of outdated treatments. New compounds with antiplasmodial activity are needed to be developed as effective drugs against malaria. The hypothesis for this project is that marine microorganisms have a high likelihood of yielding novel antiplasmodial chemotypes because of their high diversity, which has not yet been explored for antimalarial development. In this project, microbes harvested and fermented by the Harbor Branch Oceanographic Institute in Fort Pierce, Florida were explored as sources for antiplasmodial natural products. Using a SYBR Green I fluorescence-based assay, 1,000 microbial extracts were screened for inhibition of the multidrug-resistant Plasmodium falciparum strain Dd2. Dose-response analysis was performed on 46 fractions from isolates whose extracts demonstrated [greater-than or equal to] 70% inhibition of Dd2 at 1 [micro]g/mL. To evaluate cytotoxicity, the MTS cell viability assay was used to calculate IC50 of extracts from active isolates in NIH/3T3 embryonic mouse fibroblasts. Several extracts demonstrated low IC50 in Dd2 and high IC50 in 3T3, suggesting that they contain potential lead antimalarial compounds. Extracts with high selectivity indices (potent plasmodial inhibition with low mammalian toxicity) have been prioritized for dereplication, with the goal of identifying novel active components that can be developed as antimalarial drugs.
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Date Issued
2013
Identifier
CFH0004332, ucf:45035
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH0004332