Recent updates in the discovery and development of novel antimalarial drug candidates

Concerns of emerging resistance and the search for molecules with potential for single exposure radical cure and prophylaxis have spurred research into compounds with target profiles for clinical development into antimalarial drugs.

Download Full-text

Synthesis, characterization and biological activity of organometallic derivatives of the antimalarial drug mefloquine as new antischistosomal drug candidates

MedChemComm ◽

10.1039/c8md00396c ◽

2018 ◽

Vol 9 (11) ◽

pp. 1905-1909 ◽

Cited By ~ 7

Author(s):

Faustine d'Orchymont ◽

Jeannine Hess ◽

Gordana Panic ◽

Marta Jakubaszek ◽

Lea Gemperle ◽

...

Keyword(s):

Biological Activity ◽

Antimalarial Drug ◽

Biological Evaluation ◽

Design Synthesis ◽

Drug Candidates ◽

Derivatives Of

The design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the antimalarial mefloquine is described.

Download Full-text

Novel antimalarial drug targets: hope for new antimalarial drugs

Expert Review of Clinical Pharmacology ◽

10.1586/ecp.09.28 ◽

2009 ◽

Vol 2 (5) ◽

pp. 469-489 ◽

Cited By ~ 26

Author(s):

Athar Alam ◽

Manish Goyal ◽

Mohd Shameel Iqbal ◽

Chinmay Pal ◽

Sumanta Dey ◽

...

Keyword(s):

Antimalarial Drug ◽

Drug Targets ◽

Antimalarial Drugs

Download Full-text

Pharmacodynamic assays to facilitate preclinical and clinical development of pre‐ mRNA splicing modulatory drug candidates

Pharmacology Research & Perspectives ◽

10.1002/prp2.158 ◽

2015 ◽

Vol 3 (4) ◽

Cited By ~ 10

Author(s):

Yihui Shi ◽

Amanda S. Joyner ◽

William Shadrick ◽

Gustavo Palacios ◽

Chandraiah Lagisetti ◽

...

Keyword(s):

Clinical Development ◽

Mrna Splicing ◽

Drug Candidates

Download Full-text

The Position of ADME Predictions in Multi-Objective QSAR

International Journal of Quantitative Structure-Property Relationships ◽

10.4018/ijqspr.2021010101 ◽

2021 ◽

Vol 6 (1) ◽

pp. 1-8

Author(s):

Anna Tsantili-Kakoulidou

Keyword(s):

Drug Efficacy ◽

Clinical Development ◽

Efficacy And Safety ◽

Huge Amount ◽

Multi Objective ◽

Drug Candidates ◽

Drug Molecules ◽

Qsar Models ◽

Adme Properties ◽

Single Objective

ADME properties and toxicity predictions play an essential role in prioritization and optimization of drug molecules. According to recent statistics, drug efficacy and safety are principal reasons for drug failure. In this perspective, the position of ADME predictions in the evolution of traditional QSAR from the single objective of biological activity to a multi-task concept is discussed. The essential features of ADME and toxicity QSAR models are highlighted. Since such models are applied to prioritize existing or virtual project compounds with already established or predicted target affinity, a mechanistic interpretation, although desirable, is not a primary goal. However, a broad applicability domain is crucial. A future challenge with multi-objective QSAR is to adapt to the realm of big data by integrating techniques for the exploitation of the continuously increasing number of ADME data and the huge amount of clinical development endpoints for the sake of efficacy and safety of new drug candidates.

Download Full-text

Plasmodium vivax and Drug Resistance

10.5772/intechopen.97320 ◽

2021 ◽

Author(s):

Puji Budi Setia Asih ◽

Din Syafruddin

Keyword(s):

Drug Resistance ◽

Molecular Basis ◽

Indirect Evidence ◽

Antimalarial Drugs ◽

In Vivo Studies ◽

In Vitro Cultivation ◽

Radical Cure ◽

The Status

Resistance to antimalarial drugs is a threat to global efforts to eliminate malaria by 2030. Currently, treatment for vivax malaria uses chloroquine or ACT for uncomplicated P. vivax whereas primaquine is given to eliminate latent liver stage infections (a method known as radical cure). Studies on P. vivax resistance to antimalarials and the molecular basis of resistance lags far behind the P. falciparum as in vitro cultivation of the P. vivax has not yet been established. Therefore, data on the P. vivax resistance to any antimalarial drugs are generated through in vivo studies or through monitoring of antimalarial treatments in mixed species infection. Indirect evidence through drug selective pressure on the parasites genome, as evidenced by the presence of the molecular marker(s) for drug resistance in areas where P. falciparum and P. vivax are distributed in sympatry may reflect, although require validation, the status of P. vivax resistance. This review focuses on the currently available data that may represent the state-of-the art of the P. vivax resistance status to antimalarial to anticipate the challenge for malaria elimination by 2030.

Download Full-text

An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

Molecules ◽

10.3390/molecules25215182 ◽

2020 ◽

Vol 25 (21) ◽

pp. 5182

Author(s):

Chantalle Moolman ◽

Rencia van der Sluis ◽

Richard M. Beteck ◽

Lesetja J. Legoabe

Keyword(s):

Small Molecule ◽

Antimalarial Drug ◽

Kinase Inhibitors ◽

Antimalarial Drugs ◽

Next Generation ◽

Antimalarial Drug Resistance ◽

Cellular Processes ◽

Antimalarial Agents ◽

Molecule Inhibitor ◽

Multiple Stages

Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite’s life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.

Download Full-text

Targeting the IL33–NLRP3 axis improves therapy for experimental cerebral malaria

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801737115 ◽

2018 ◽

Vol 115 (28) ◽

pp. 7404-7409 ◽

Cited By ~ 15

Author(s):

Patrick Strangward ◽

Michael J. Haley ◽

Manuel G. Albornoz ◽

Jack Barrington ◽

Tovah Shaw ◽

...

Keyword(s):

Cerebral Malaria ◽

Antimalarial Drug ◽

Time Course ◽

Treatment Success ◽

Neurological Complication ◽

Recovery Period ◽

Antimalarial Drugs ◽

Inflammasome Activation ◽

Bioinformatics Analyses ◽

Experimental Cerebral Malaria

Cerebral malaria (CM) is a serious neurological complication caused by Plasmodium falciparum infection. Currently, the only treatment for CM is the provision of antimalarial drugs; however, such treatment by itself often fails to prevent death or development of neurological sequelae. To identify potential improved treatments for CM, we performed a nonbiased whole-brain transcriptomic time-course analysis of antimalarial drug chemotherapy of murine experimental CM (ECM). Bioinformatics analyses revealed IL33 as a critical regulator of neuroinflammation and cerebral pathology that is down-regulated in the brain during fatal ECM and in the acute period following treatment of ECM. Consistent with this, administration of IL33 alongside antimalarial drugs significantly improved the treatment success of established ECM. Mechanistically, IL33 treatment reduced inflammasome activation and IL1β production in microglia and intracerebral monocytes in the acute recovery period following treatment of ECM. Moreover, treatment with the NLRP3-inflammasome inhibitor MCC950 alongside antimalarial drugs phenocopied the protective effect of IL33 therapy in improving the recovery from established ECM. We further showed that IL1β release from macrophages was stimulated by hemozoin and antimalarial drugs and that this was inhibited by MCC950. Our results therefore demonstrate that manipulation of the IL33–NLRP3 axis may be an effective therapy to suppress neuroinflammation and improve the efficacy of antimalarial drug treatment of CM.

Download Full-text

Cheminformatics techniques in antimalarial drug discovery and development from natural products 1: basic concepts

Physical Sciences Reviews ◽

10.1515/psr-2018-0130 ◽

2019 ◽

Vol 4 (7) ◽

Author(s):

Samuel Egieyeh ◽

Sarel F. Malan ◽

Alan Christoffels

Keyword(s):

Natural Products ◽

Drug Development ◽

Antimalarial Drug ◽

Drug Discovery And Development ◽

Drug Candidates ◽

Structure Activity ◽

Preclinical And Clinical Studies ◽

Research Cost

Abstract A large number of natural products, especially those used in ethnomedicine of malaria, have shown varying in vitro antiplasmodial activities. Facilitating antimalarial drug development from this wealth of natural products is an imperative and laudable mission to pursue. However, limited manpower, high research cost coupled with high failure rate during preclinical and clinical studies might militate against the pursuit of this mission. These limitations may be overcome with cheminformatic techniques. Cheminformatics involves the organization, integration, curation, standardization, simulation, mining and transformation of pharmacology data (compounds and bioactivity) into knowledge that can drive rational and viable drug development decisions. This chapter will review the application of cheminformatics techniques (including molecular diversity analysis, quantitative-structure activity/property relationships and Machine learning) to natural products with in vitro and in vivo antiplasmodial activities in order to facilitate their development into antimalarial drug candidates and design of new potential antimalarial compounds.

Download Full-text