Phase 1 study designed to evaluate the relative bioavailability of a single dose of a test formulation, DSM265-TPGS 34% SDD powder in comparison with a reference DSM265 25% SDD powder formulation used in early clinical trials.

Start Date03 Oct 2018

Sponsor / Collaborator

MMV Medicines for Malaria Venture

[+1]

PACTR201712002879427 / SuspendedNot ApplicableIIT

Randomized, placebo-controlled, double-blind, three-arm, clinical trial to assess safety, tolerability and protective efficacy of PfSPZ-CVac and PfSPZ Vaccine in 1-12 years old African children naturally exposed to malaria parasites

Start Date01 Mar 2018

Sponsor / Collaborator-

NCT03083847 / CompletedPhase 1IIT

Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Phase 1 Dose Escalation Trial to Determine Safety and Development of Protective Efficacy After Exposure to Only Pre-erythrocytic Stages of Plasmodium Falciparum

Background:
People get malaria from bites from infected mosquitos. Researchers are studying a vaccine strategy. They will give people malaria parasites by injecting them with live infectious malaria parasites with antimalarial medications and then see if this strategy prevents malaria infection while off antimalarial medications.
Objective:
To see if combining a high dose of live, infectious malaria parasites (known as Sanaria PfSPZ Challenge) and two FDA approved drugs that kill malaria parasites (pyrimethamine [PYR] OR chloroquine [CQ]) is safe and can provide people protection against malaria.
Eligibility:
Healthy adults ages 18-50 who:
are not pregnant or breastfeeding or planning on becoming pregnant while in the study
are not infected with HIV, Hepatitis B or Hepatitis C
have reliable early morning access to the NIH Clinical Center
are able to come to the outpatient clinic frequently, sometimes daily
have not been diagnosed with malaria within the past 10 years
Design:
Participants will be screened with medical history and physical exam. They will have heart, blood, and urine tests.
Participants will have blood drawn for tests at most visits.
Participants will keep track of their temperature and symptoms during some sections of the study.
Participants will join one part of the study.
Part 1 is one month:
Participants will get the parasites by an injection into a vein on day 1 and receive antimalarial medications.
They will have daily visits on days 7-14
They will take another antimalarial at visits on days 15-17.
The final visit will be on day 29.
Part 2 is seven months:
For the first 3 months, participants will get the parasite injection into a vein for 3 injections in total. Each injection will occur once per month while taking an antimalarial drug.
They will have daily visits on days 7-14 after the first injection, and on days 7-11 after the second and third injection.
They will have a final (fourth) injection around month 6 without any antimalarial medication.
After this fourth injection, participants may have up to 21 daily visits from day 7 after injection until end of study.
Part 3 is one month:
Participants will get the parasites by injection into a vein on day 1 without antimalarial medications.
They will have visits almost every day starting day 7 from injection.
They will take an antimalarial medication when they are diagnosed with malaria
They will return for final end of study visit on days 27-29.

Start Date05 Jun 2017

Sponsor / Collaborator

National Institute of Allergy & Infectious Diseases

[+1]

100 Clinical Results associated with PfDHODH

100 Translational Medicine associated with PfDHODH

0 Patents (Medical) associated with PfDHODH

Literatures (Medical) associated with PfDHODH

01 Dec 2024·Bioorganic Chemistry

A comprehensive review of synthetic strategies and SAR studies for the discovery of PfDHODH inhibitors as antimalarial agents. Part 2: Non-DSM compounds

Review

Author: Vyas, Vivek K ; Lolli, Marco L. ; Sharma, Manmohan ; Lolli, Marco L ; Vyas, Vivek K.

Malaria remains a severe global health concern, with 249 million cases reported in 2022, according to the World Health Organization (WHO) [1]. PfDHODH is an essential enzyme in malaria parasites that helps to synthesize certain building blocks for their growth and development. It has been confirmed that targeting Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme could lead to new and effective antimalarial drugs. Inhibitors of PfDHODH have shown potential for slowing down parasite growth during both the blood and liver stages. Over the last two decades, many species selective PfDHODH inhibitors have been designed, including DSM compounds and other non-DSM compounds. In the first chapter [2] of this review, we have reviewed all synthetic schemes and structure-activity relationship (SAR) studies of DSM compounds. In this second chapter, we have compiled all the other non-DSM PfDHODH inhibitors based on dihydrothiophenones, thiazoles, hydroxyazoles, and N-alkyl-thiophene-2-carboxamides. The review not only offers an insightful overview of the synthetic methods employed but also explores into alternative routes and innovative strategies involving different catalysts and chemical reagents. A critical aspect covered in the review is the SAR studies, which provide a comprehensive understanding of how structural modifications impact the efficacy of PfDHODH inhibitors and challenges related to the discovery of PfDHODH inhibitors. This information is invaluable for scientists engaged in the development of new antimalarial drugs, offering insights into the most promising scaffolds and their synthetic techniques.

01 Mar 2024·European Journal of Medicinal Chemistry

Discovery of new piperaquine hybrid analogs linked by triazolopyrimidine and pyrazolopyrimidine scaffolds with antiplasmodial and transmission blocking activities

Article

Author: Nogueira, Fatima ; Pinheiro, Luiz C S ; Duarte, Denise ; Nonato, M Cristina ; de Souza, Guilherme E ; Zapata, Luana ; Aguiar, Anna C C ; Ferreira, Maria de Lourdes G ; de Souza, Juliana O ; Guido, Rafael V C ; Feitosa, Livia M ; Franca, Rodolfo Rodrigo F ; Morais, Ines ; Maluf, Sarah El Chamy ; Boechat, Nubia

The World Health Organization (WHO) estimated that there were 247 million malaria cases in 2021 worldwide, representing an increase in 2 million cases compared to 2020. The urgent need for the development of new antimalarials is underscored by specific criteria, including the requirement of new modes of action that avoid cross-drug resistance, the ability to provide single-dose cures, and efficacy against both assexual and sexual blood stages. Motivated by the promising results obtained from our research group with [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives, we selected these molecular scaffolds as the foundation for designing two new series of piperaquine analogs as potential antimalarial candidates. The initial series of hybrids was designed by substituting one quinolinic ring of piperaquine with the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine nucleus. To connect the heterocyclic systems, spacers with 3, 4, or 7 methylene carbons were introduced at the 4 position of the quinoline. In the second series, we used piperazine as a spacer to link the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine group to the quinoline core, effectively merging both pharmacophoric groups via a rigid spacer. Our research efforts yielded promising compounds characterized by low cytotoxicity and selectivity indices exceeding 1570. These compounds displayed potent in vitro inhibitory activity in the low nanomolar range against the erythrocytic form of the parasite, encompassing both susceptible and resistant strains. Notably, these compounds did not show cross-resistance with either chloroquine or established P. falciparum inhibitors. Even though they share a pyrazolo- or triazolo-pyrimidine core, enzymatic inhibition assays revealed that these compounds had minimal inhibitory effects on PfDHODH, indicating a distinct mode of action unrelated to targeting this enzyme. We further assessed the compounds' potential to interfere with gametocyte and ookinete infectivity using mature P. falciparum gametocytes cultured in vitro. Four compounds demonstrated significant gametocyte inhibition ranging from 58 % to 86 %, suggesting potential transmission blocking activity. Finally, we evaluated the druggability of these new compounds using in silico methods, and the results indicated that these analogs had favorable physicochemical and ADME (absorption, distribution, metabolism, and excretion) properties. In summary, our research has successfully identified and characterized new piperaquine analogs based on [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine scaffolds and has demonstrated their potential as promising candidates for the development of antimalarial drugs with distinct mechanisms of action, considerable selectivity, and P. falciparum transmission blocking activity.

29 Dec 2023·Journal of Biomolecular Structure and Dynamics

Antiplasmodial activity of coumarins isolated from Polygala boliviensis : in vitro and in silico studies

Article

Author: Alves, Clayton Queiroz ; Leite, Franco Henrique Andrade ; Moreira, Paulo Otávio Lourenço ; de Souza, Jéssica Lima ; Brandão, Hugo Neves ; dos Santos, Cleydson Breno Rodrigues ; Costa, David Bacelar ; da Costa, Diego Mota ; Fonseca, Amanda Luisa da ; da Silva, Danielle Figuerêdo ; Varotti, Fernando de Pilla ; Cruz, Jorddy Neves

Polygala boliviensis is found in the Brazilian semiarid region. This specie is little chemically and biologically studied. Polygala spp. have different metabolites, especially coumarins. Studies indicate that coumarins have antimalarial potential, denoting the importance of researching new active compounds from plants, since the resistance of Plasmodium strains to conventional therapy has increased. The present study aimed to evaluate the antiplasmodial activity of auraptene and poligalen against a chloroquine-resistant strain of Plasmodium falciparum. Coumarins were isolated from P. boliviensis by open column chromatography and identified by Nuclear Magnetic Resonance Spectroscopy. A cytotoxicity assay was carried out using MTT test, and the in vitro antiplasmodial activity was evaluated using the W2 strain. The antiplasmodial activity results found were IC₅₀=0.171 ± 0.016 for auraptene and 0.164 ± 0.012 for poligalen; the selectivity indexes were 78.71 and 609.76, respectively. Inverse virtual screening in the BRAMMT database by OCTOPUS 1.2 was applied to coumarins to find potential P. falciparum targets and showed higher affinity energy of auraptene for purine nucleoside phosphorylase (PfPNP) and of poligalen for dihydroorotate dehydrogenase (PfDHODH). Molecular Dynamics studies (MD and MM-GBSA) approach were applied to calculate binding energies against selected P. falciparum targets and showed that all coumarins were stable at the binding site during simulations. Furthermore, energies were favorable for complexation. This is the first report of auraptene in P. boliviensis species and of in vitro antiplasmodial activity of auraptene and poligalen. In silico studies indicated that the mechanism of action of coumarins is the inhibition of PfPNP and PfDHODH.Communicated by Ramaswamy H. Sarma.

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