Current leishmaniasis drug discovery

Pinheiro, Alessandra C.; Souza, Marcus V. N. de

doi:10.1039/d1md00362c

Cited by 25 publications

(15 citation statements)

References 108 publications

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“…Unfortunately, the process is still far from optimal, with failures assigned to the drug discovery invoking imperfect disease models, lack of efficacy and the appearance of resistance, toxicity issues, differences in human pharmacokinetics compared to the murine models used in optimization studies, the recursive discovery of drugs acting against the same targets, and the increasing evidence of persisters. 6,[15][16][17]23,24 Complementary approaches for drug discovery include the repurposing of drugs from other diseases which can speed up the development as they are already optimized and assessed for good pharmacokinetics and toxicity, and structure-based drug discovery methodologies. In addition to these empirical approaches, in silico methods have also been applied to assist in the discovery of new drugs against leishmaniasis and other NTDs.…”

Section: The Discovery Of New Antileishmanial Drugsmentioning

confidence: 99%

“…In any case, after initial discoveries of lead compounds of sufficient potency, the trend is to address pharmacokinetic improvements afterward, as safe oral drugs are a must. Unfortunately, the process is still far from optimal, with failures assigned to the drug discovery invoking imperfect disease models, lack of efficacy and the appearance of resistance, toxicity issues, differences in human pharmacokinetics compared to the murine models used in optimization studies, the recursive discovery of drugs acting against the same targets, and the increasing evidence of persisters 6,15–17,23,24 . Complementary approaches for drug discovery include the repurposing of drugs from other diseases which can speed up the development as they are already optimized and assessed for good pharmacokinetics and toxicity, and structure‐based drug discovery methodologies.…”

Section: Introductionmentioning

confidence: 99%

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Experimental structure based drug design (SBDD) applications for anti‐leishmanial drugs: A paradigm shift?

Marín,

López,

Gallego‐Yerga

et al. 2023

Medicinal Research Reviews

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Leishmaniasis is a group of neglected tropical diseases caused by at least 20 species of Leishmania protozoa, which are spread by the bite of infected sandflies. There are three main forms of the disease: cutaneous leishmaniasis (CL, the most common), visceral leishmaniasis (VL, also known as kala‐azar, the most serious), and mucocutaneous leishmaniasis. One billion people live in areas endemic to leishmaniasis, with an annual estimation of 30,000 new cases of VL and more than 1 million of CL. New treatments for leishmaniasis are an urgent need, as the existing ones are inefficient, toxic, and/or expensive. We have revised the experimental structure‐based drug design (SBDD) efforts applied to the discovery of new drugs against leishmaniasis. We have grouped the explored targets according to the metabolic pathways they belong to, and the key achieved advances are highlighted and evaluated. In most cases, SBDD studies follow high‐throughput screening campaigns and are secondary to pharmacokinetic optimization, due to the majoritarian belief that there are few validated targets for SBDD in leishmaniasis. However, some SBDD strategies have significantly contributed to new drug candidates against leishmaniasis and a bigger number holds promise for future development.

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Section: The Discovery Of New Antileishmanial Drugsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Experimental structure based drug design (SBDD) applications for anti‐leishmanial drugs: A paradigm shift?

Marín,

López,

Gallego‐Yerga

et al. 2023

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

“…Leishmaniasis is affected by poor nutrition, poor sanitation, a weak immune system, and a lack of preventive measures [ 9 ]. This parasite occurs in Asia, Africa, the Americas, and the Mediterranean region.…”

Section: Introductionmentioning

confidence: 99%

Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms

Zhang

et al. 2023

Marine Drugs

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Parasitic diseases still threaten human health. At present, a number of parasites have developed drug resistance, and it is urgent to find new and effective antiparasitic drugs. As a rich source of biological compounds, marine natural products have been increasingly screened as candidates for developing new antiparasitic drugs. The literature related to the study of the antigenic animal activity of marine natural compounds from invertebrates and microorganisms was selected to summarize the research progress of marine compounds and the structure–activity relationship of these compounds in the past five years and to explore the possible sources of potential antiparasitic drugs for parasite treatment.

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“…Neglected tropical diseases caused by kinetoplastid parasites (i.e., Trypanosoma cruzi, Trypanosoma brucei, and Leishmania) are a great cause of suffering around the world. American and African trypanosomiases, as well as leishmaniasis, threaten millions of people mainly in the least developed countries. – Available therapies to treat these illnesses are not satisfactory as they often present poor efficacy against drug-resistant parasite strains or a particular stage of the disease or patient condition (e.g., chronic Chagas disease, late-stage rhodesiense sleeping sickness, and HIV/leishmaniasis coinfection), and habitually require prolonged treatment regimens and high doses, with associated severe side effects. – In addition, T. brucei rhodesiense, T.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biophysical and Biological Studies of N-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites

Nué-Martinez,

Cisneros,

Moreno-Blázquez

et al. 2023

J. Med. Chem.

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The AT-rich mitochondrial DNA (kDNA) of trypanosomatid parasites is a target of DNA minor groove binders. We report the synthesis, antiprotozoal screening, and SAR studies of three series of analogues of the known antiprotozoal kDNA binder 2- ((4-(4-((4,5-Bis(2-aminoimidazolines) (1) and bis(2-aminobenzimidazoles) (2) showed micromolar range activity against Trypanosoma brucei, whereas bisarylimidamides (3) were submicromolar inhibitors of T. brucei, Trypanosoma cruzi, and Leishmania donovani. None of the compounds showed relevant activity against the urogenital, nonkinetoplastid parasite Trichomonas vaginalis. We show that series 1 and 3 bind strongly and selectively to the minor groove of AT DNA, whereas series 2 also binds by intercalation. The measured pK a indicated different ionization states at pH 7.4, which correlated with the DNA binding affinities (ΔT m ) for series 2 and 3. Compound 3a, which was active and selective against the three parasites and displayed adequate metabolic stability, is a fine candidate for in vivo studies.

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Current leishmaniasis drug discovery

Abstract: This review explores the wide range of compounds that are being identified as antileishmanial drug prototypes, summarize the advances in identifying innovative treatments and explore the state-of-art of vaccines and immunomodulation strategies.

Cited by 25 publications

References 108 publications

Experimental structure based drug design (SBDD) applications for anti‐leishmanial drugs: A paradigm shift?

Experimental structure based drug design (SBDD) applications for anti‐leishmanial drugs: A paradigm shift?

Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms

Synthesis and Biophysical and Biological Studies of N-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites

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