Discovery of New Compounds Active against Plasmodium falciparum by High Throughput Screening of Microbial Natural Products

Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products.     

Recent advances in novel heterocyclic scaffolds for the treatment of drug-resistant malaria

Malaria is a major public health problem all over the world, particularly in tropical and subtropical countries due to the development of resistance and most deadly infection is caused by Plasmodium falciparum. There is a direct need for the discovery of new drugs with unique structures and mechanism of action to treat sensitive and drug-resistant strains of various plasmodia for radical cure of this disease. Traditional compounds such as quinine and related derivatives represent a major source for the development of new drugs. This review presents recent modifications of 4-aminoquinoline and 8-aminoquinolone rings as leads to novel active molecules which are under clinical trials. The review also encompasses the other heterocyclic compounds emerged as potential antimalarial agents with promising results such as acridinediones and acridinone analogues, pyridines and quinolones as antimalarials. Miscellaneous heterocyclics such as tetroxane derivatives, indole derivatives, imidazolopiperazine derivatives, biscationic choline-based compounds and polymer-linked combined antimalarial drugs are also discussed. At last brief introduction to heterocyclics in natural products is also reviewed. Most of them have been under clinical trials and found to be promising in the treatment of drug-resistant strains of Plasmodium and others can be explored for the same purpose.     

Natural products for cancer chemotherapy

For over 40 years, natural products have served us well in combating cancer. The main sources of these successful compounds are microbes and plants from the terrestrial and marine environments. The microbes serve as a major source of natural products with anti‐tumour activity. A number of these products were first discovered as antibiotics. Another major contribution comes from plant alkaloids, taxoids and podophyllotoxins. A vast array of biological metabolites can be obtained from the marine world, which can be used for effective cancer treatment. The search for novel drugs is still a priority goal for cancer therapy, due to the rapid development of resistance to chemotherapeutic drugs. In addition, the high toxicity usually associated with some cancer chemotherapy drugs and their undesirable side‐effects increase the demand for novel anti‐tumour drugs active against untreatable tumours, with fewer side‐effects and/or with greater therapeutic efficiency. This review points out those technologies needed to produce the anti‐tumour compounds of the future.     

Allenic and cumulenic lipids

Nowadays, about 200 natural allenic metabolites, more than 2700 synthetic allenic compounds, and about 1300 cumulenic structures are known. The present review describes research on natural as well as some biological active allenic and cumulenic lipids and related compounds isolated from different sources. Intensive searches for new classes of pharmacologically potent agents produced by living organisms have resulted in the discovery of dozens of such compounds possessing high anticancer, cytotoxic, antibacterial, antiviral, and other activities. Known allenic and cumulenic compounds can be subdivided on several structural classes: fatty acids, hydrocarbons, terpenes, steroids, carotenoids, marine bromoallenes, peptides, aromatic, cumulenic, and miscellaneous compounds. This review emphasizes the role of natural and synthetic allenic and cumulenic lipids and other related compounds as an important source of leads for drug discovery.     

Synthetic medicinal chemistry of selected antimalarial natural products

Natural products remain a rich source of novel molecular scaffolds for novel antimalarial agents in the fight against malaria. This has been well demonstrated in the case of quinine and artemisinin both of which have served as templates for the development of structurally simpler analogues that either served or continue to serve as effective antimalarials. This review will expound on these two natural products as well as other selected natural products that have served either as antimalarial agents or as potential lead compounds in the development of antimalarial drugs.     

Drug discovery from natural products

Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in actinomycetes, exploring the marine environment and applying new screening technologies. In many instances, the discovery of a novel natural product serves as a tool to better understand targets and pathways in the disease process. This review describes recent progress in drug discovery from natural sources including several examples of compounds that inhibit novel drug targets.     

Plant natural products: from traditional compounds to new emerging drugs in cancer therapy

Natural products are chemical compounds or substances produced naturally by living organisms. With the development of modern technology, more and more plant extracts have been found to be useful to medical practice. Both micromolecules and macromolecules have been reported to have the ability to inhibit tumour progression, a novel weapon to fight cancer by targeting its 10 characteristic hallmarks. In this review, we focus on summarizing plant natural compounds and their derivatives with anti‐tumour properties, into categories, according to their potential therapeutic strategies against different types of human cancer. Taken together, we present a well‐grounded review of these properties, hoping to shed new light on discovery of novel anti‐tumour therapeutic drugs from known plant natural sources.     

The potential of seaweed as a source of drugs for use in cancer chemotherapy

This review discusses studies on marine macroalgae that have been investigated for their potential as sources of novel anti-cancer drugs. The review highlights the very large number of studies of crude, partially purified and purified seaweed extracts, collected from many locations, which have shown potential as sources of potent anti-cancer drugs when tested in vitro and/or in vivo. The activity of polysaccharides, polyphenols, proteinaceous molecules, carotenoids, alkaloids, terpenes and others is described here. In some reports, mechanistic studies have identified specific inhibitory activity on a number of key cellular processes including apoptosis pathways, telomerase and tumour angiogenesis. However, despite the potential shown by these studies, translation to clinically useful preparations is almost non-existent. It is hoped this review will serve as a source document and guide for those carrying out research into the potential use of macroalgae as a source of novel anti-cancer agents.     

Bioactive Peptides from Marine Ascidians and Future Drug Development–A Review

Marine ascidians are considered as one of the richest sources of bioactive compounds. The extraction and utilization of marine peptides have been attracted much attention owing to their potential health benefits. Most of the bioactive compounds from marine ascidians are already in different phases of the clinical and preclinical pipeline. They can be used in different functional and nutraceutical values due to their antineoplastic, antihypertensive, antioxidant, and antimicrobial properties. The screening in vivo and in vitro bioassays are coupled to the purification process for the exploration of its biological interest which is of great value. The growing significance to study marine natural products results from the discovery of novel pharmacological tools including potent anticancer drugs and other drugs are in clinical/pre-clinical trials. The present review highlights the recent research progress in marine ascidians’ peptides and its prospects for the future pharmaceutical development.     

Antibacterial plant compounds,extracts and essential oils: An updated review on their effects and putative mechanisms of action

Background: Antibiotic-resistant bacteria pose a global health threat. Traditional antibiotics can lose their effectiveness, and the development of novel effective antimicrobials has become a priority in recent years. In this area, plants represent an invaluable source of antimicrobial compounds with vast therapeutic potential.Purpose: To review the full possible spectrum of plant antimicrobial agents (plant compounds, extracts and essential oils) discovered from 2016 to 2021 and their potential to decrease bacterial resistance. Their activities against bacteria, with special emphasis on multidrug resistant bacteria, mechanisms of action, possible combinations with traditional antibiotics, roles in current medicine and future perspectives are discussed.Methods: Studies focusing on the antimicrobial activity of compounds of plant origin and their mechanism of action against bacteria were identified and summarized, including contributions from January 2016 until January 2021. Articles were extracted from the Medline database using PubMed search engine with relevant keywords and operators.Results: The search yielded 11,689 articles from 149 countries, of which 101 articles were included in this review. Reports from 41 phytochemicals belonging to 20 families were included. Reports from plant extracts and essential oils from 39 plant species belonging to 17 families were also included. Polyphenols and terpenes were the most active phytochemicals studied, either alone or as a part of plant extracts or essential oils. Plasma membrane disruption was the most common mechanism of antimicrobial action. Number and position of phenolic hydroxyl groups, double bonds, delocalized electrons and conjugation with sugars in the case of flavonoids seemed to be crucial for antimicrobial capacity. Combinations of phytochemicals with beta-lactam antibiotics were the most studied, and the inhibition of efflux pumps was the most common synergistic mechanism.Conclusion: In recent years, terpenes, flavones, flavonols and some alkaloids and phenylpropanoids, either isolated or as a part of extracts, have shown promising antimicrobial activity, being membrane disruption their most common mechanism. However, their utilization as appropriate antimicrobials need to be boosted by means of new omics technologies and network pharmacology to find the most effective combinations among them or in combination with antibiotics.     

Drug discovery for malaria: a very challenging and timely endeavor

The prevalence of resistance to known antimalarial drugs has resulted in the expansion of antimalarial drug discovery efforts. Academic and nonprofit institutions are partnering with the pharmaceutical industry to develop new antimalarial drugs. Several new antimalarial agents are undergoing clinical trials, mainly those resurrected from previous antimalarial drug discovery programs. Novel antimalarials are being advanced through the drug development process, of course, with the anticipated high failure rate typical of drug discovery. Many of these are summarized in this review. Mechanisms for funding antimalarial drug discovery and genomic information to aid drug target selection have never been better. It remains to be seen whether ongoing efforts will be sufficient for reducing malaria burden in the developing world.     

Marine Natural Products: The Important Resource of Biological Insecticide

Due to the unique environmental conditions and vast territory, marine habitat breeds more abundant biological resources than terrestrial environment. Massive marine biological species provide valuable resources for obtaining a large number of natural products with diverse structure and excellent activity. In recent years, new breakthroughs have been made in the application of marine natural products in drug development. In addition, the use of marine natural products to develop insecticides and other pesticide products has also been widely concerned. Targeting marine plants, animals, and microorganisms, we have collected information on marine natural products with insecticidal activity for nearly decade, including alkaloids, terpenes, flavonoids and phenols fatty acids, peptides, and proteins, et al. In addition, some active crude extracts are also included. This review describes the insecticidal activities of marine natural products and their broad applications for future research in agriculture and health.     

Photosynthetic marine organisms as a source of anticancer compounds

Since early human history, plants have served as the most important source of medicinal natural products, and even in the “synthetic age” the majority of lead compounds for pharmaceutical development remain of plant origin. In the marine realm, algae and seagrasses were amongst the first organisms investigated by marine natural products scientists on their quest for novel pharmaceutical compounds. Forty years after the pioneering work in the field of marine drug discovery began, the biodiversity of marine organisms investigated as potential sources of anticancer, anti-inflammatory, and antibiotic compounds has increased tremendously. Nonetheless, marine plants are still an important source of novel secondary metabolites with interesting biomedical properties. The present review focuses on the antitumour properties of compounds isolated from marine algae, phytoplankton, mangroves, seagrasses, or cordgrasses. Compounds produced by marine epi- or endophytic fungi are also discussed.     

Recent advances in the fight against leishmaniasis with natural products

The active compounds obtained from some medicinal plants used traditionally worldwide for the treatment of leishmaniasis are reviewed. Among these active molecules, described in recent literature are quinoline alkaloids such as alkyl-2 quinoline and aryl-2 quinoline from Galipea longiflora, isoquinoline alkaloids such as isoguattouregidine from Guatteria foliosa, indole alkaloids such as conodurine and gabunine from Pescheiera van heurkii, terpenes such as jatrogrossidione from Jatropha grossidentata, acetogenins such as senegalene from Annona senegalensis and lignans such as (+)nyasol from Asparagus africanus. Other natural compounds with antileishmanial activity are coumarins, chalcones, lactones, tetralones and saponins. Some of them are known antiprotozoal natural products. These compounds could be used as templates to discover new and effective drugs against leishmaniasis.     

Naturally occurring plant isoquinoline N-oxide alkaloids: Their pharmacological and SAR activities

The present review describes research on novel natural isoquinoline alkaloids and their N-oxides isolated from different plant species. More than 200 biological active compounds have shown confirmed antimicrobial, antibacterial, antitumor, and other activities. The structures, origins, and reported biological activities of a selection of isoquinoline N-oxides alkaloids are reviewed. With the computer program PASS some additional SAR (structure–activity relationship) activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of isoquinoline N-oxides alkaloids as an important source of leads for drug discovery.     

A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P₀) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task.     

Marine pharmacology in 2007–8: Marine compounds with antibacterial,anticoagulant, antifungal,anti-inflammatory,antimalarial, antiprotozoal,antituberculosis, and antiviral activities; affecting the immune and nervous system,and other miscellaneous mechanisms of action

The peer-reviewed marine pharmacology literature in 2007–8 is covered in this review, which follows a similar format to the previous 1998–2006 reviews of this series. The preclinical pharmacology of structurally characterized marine compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 74 marine natural products. Additionally, 59 marine compounds were reported to affect the cardiovascular, immune and nervous systems as well as to possess anti-inflammatory effects. Finally, 65 marine metabolites were shown to bind to a variety of receptors and miscellaneous molecular targets, and thus upon further completion of mechanism of action studies, will contribute to several pharmacological classes. Marine pharmacology research during 2007–8 remained a global enterprise, with researchers from 26 countries, and the United States, contributing to the preclinical pharmacology of 197 marine compounds which are part of the preclinical marine pharmaceuticals pipeline. Sustained preclinical research with marine natural products demonstrating novel pharmacological activities, will probably result in the expansion of the current marine pharmaceutical clinical pipeline, which currently consists of 13 marine natural products, analogs or derivatives targeting a limited number of disease categories.     

The Discovery of Medicines from Plants: A Current Biological Perspective1

The Discovery of Medicines from Plants: A Current Biological Perspective. The last 50 years have seen tremendous innovations in the process of discovering novel bioactive compounds from plants. Every stage of the natural products discovery and development pipeline has seen major advances, so as a result, today it is possible to evaluate large numbers of plant extracts efficiently and in more effective ways against a wider array of disease targets. Despite all of these technological advances and numerous large-scale discovery efforts, the number of new drugs developed as natural products from plants to reach the market has been surprisingly low, very different from the continuing productive discovery work from microbes. The innovations in the discovery process are reviewed, possible explanations for low success of recent discovery efforts are explored, and an effort is made to estimate the future potential of plants as a discovery resource. It may be that the low rate of discovery during this developmental period of natural products discovery is a consequence of technological limitations of the discovery process rather than a lack of interesting compounds in plants, and that even when necessary assumptions are taken into account, conservative estimates would indicate great potential for the discovery of new drugs from plants.     

Plant Derived Antimalarial Agents: New Leads and Challenges

New treatments for malaria are urgently needed due to the increasing problem of drug-resistance in malaria parasites. The long-established use of quinine and the more recent introduction of artemisinin and its derivatives as highly effective antimalarials demonstrates that plant species are an important resource for the discovery of new antimalarial agents. Furthermore, many plant species continue to be used in traditional medicines for the treatment of malaria and many people depend on such remedies as they cannot afford and/or do not have access to effective antimalarial drugs. In this paper the potential of plant species to yield new leads to antimalarial drugs will be illustrated with reference to cryptolepine, the main alkaloid present in the species, Cryptolepis sanguinolenta. In addition to this approach, there is currently increasing interest in the use and development of traditional herbal remedies for the treatment of malaria as these may have the potential to provide affordable antimalarial treatment for many who cannot afford the drugs needed to treat chloroquine-resistant Plasmodium falciparum infections. However, little is known with respect to the efficacy and safety of traditional antimalarials and clinical studies are urgently needed to establish their value. Some of the issues pertinent to this area will be briefly reviewed and it is hoped that this will stimulate further discussion and research on this important topic.     

Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part I: Aspidosperma nitidum (Benth) used as a remedy to treat fever and malaria in the Amazon

Infusions of Aspidosperma nitidum (Apocynaceae) wood bark are used to treat fever and malaria in the Amazon Region. Several species of this family are known to possess indole alkaloids and other classes of secondary metabolites, whereas terpenoids, an inositol and the indole alkaloids harmane-3 acid and braznitidumine have been described in A. nitidum . In the present study, extracts from the wood bark, leaves and branches of this species were prepared for assays against malaria parasites and cytotoxicity testing using human hepatoma and normal monkey kidney cells. The wood bark extracts were active against Plasmodium falciparum and showed a low cytotoxicity in vitro, whereas the leaf and branch extracts and the pure alkaloid braznitidumine were inactive. A crude methanol extract was subjected to acid-base fractionation aimed at obtaining alkaloid-rich fractions, which were active at low concentrations against P. falciparum and in mice infected with and sensitive Plasmodium berghei parasites. Our data validate the antimalarial usefulness of A. nitidum wood bark, a remedy that can most likely help to control malaria. However, the molecules responsible for this antimalarial activity have not yet been identified. Considering their high selectivity index, the alkaloid-rich fractions from the plant bark might be useful in the development of new antimalarials.