Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents

Hammill, Jared T.; Sviripa, Vitaliy M.; Kril, Liliia M.; Ortiz, Diana; Fargo, Corinne M.; Kim, Ho Shin; Chen, Yizhe; Rector, Jonah; Rice, Amy L.; Domagalska, Malgorzata A.; Begley, Kristin L.; Liu, Chunming; Dujardin, Jean Claude; Watt, David S.; Landfear, Scott M.; Guy, R. Kiplin

doi:10.1021/acs.jmedchem.1c00813

Cited by 10 publications

(5 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In Vivo Antileishmanial Efficacy of TAs. Given the promising antileishmanial potency of a number of TAs against L. mexicana and L. donovani along with a favorable TI against J774A.1 macrophage lines, and a favorable combination of good physicochemical properties, an in vivo proof of concept study in a well-established murine model of cutaneous leishmaniasis using BALB/c mice infected by footpad injection 52 was undertaken with 3 promising and representative TAs 95, 101, and 110. These compounds were chosen because they had a combination of properties suggesting potential in vivo efficacy, including good in vitro potency, strong TI, and acceptable in vitro metabolic stability, with 110 being the most promising by these criteria.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents

Kancharla,

Ortiz,

Fargo

et al. 2024

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure–activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

show abstract

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents

Kancharla,

Ortiz,

Fargo

et al. 2024

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hammill et al continued their previous work by developing a novel series of 3-arylquinoline derivatives and evaluating them for their antileishmanial potential against L. mexicana intracellular amastigotes [ 66 ]. In this work, a phenotypic high-throughput screening was performed to identify novel antileishmanial leads, with more than 100 molecules being evaluated, leading to further dose–response assays for the most promising antileishmanial agents.…”

Section: Quinolines As Antileishmanial Agentsmentioning

confidence: 99%

Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective

Silva,

Pinto,

Fernandes

et al. 2024

Pharmaceuticals

View full text Add to dashboard Cite

Since the beginning of the XXI century, Leishmaniasis has been integrated into the World Health Organization’s list of the 20 neglected tropical diseases, being considered a public health issue in more than 88 countries, especially in the tropics, subtropics, and the Mediterranean area. Statistically, this disease presents a world prevalence of 12 million cases worldwide, with this number being expected to increase shortly due to the 350 million people considered at risk and the 2–2.5 million new cases appearing every year. The lack of an appropriate and effective treatment against this disease has intensified the interest of many research groups to pursue the discovery and development of novel treatments in close collaboration with the WHO, which hopes to eradicate it shortly. This paper intends to highlight the quinoline scaffold’s potential for developing novel antileishmanial agents and provide a set of structural guidelines to help the research groups in the medicinal chemistry field perform more direct drug discovery and development programs. Thus, this review paper presents a thorough compilation of the most recent advances in the development of new quinoline-based antileishmanial agents, with a particular focus on structure–activity relationship studies that should be considerably useful for the future of the field.

show abstract

“…Antifungal azoles work by inhibiting the enzyme sterol 14ademethylase in Leishmania parasites [21]. Aryl Quinoline inhibits the sterol biosynthesis pathway in L. braziliensis promastigotes [30]. The mode of action includes disruption of parasite bioenergetics by disruption of mitochondrial electrochemical potential, alkalinization of acidocalcisomes, and suppression of the ergosterol biosynthetic pathway in promastigote forms [31].…”

Section: Drug Candidates Targeting Metabolic Pathways Of Leishmania 2...mentioning

confidence: 99%

Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

2022

View full text Add to dashboard Cite

Leishmaniasis is a tropical disease caused by a protozoan parasite Leishmania that is transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against leishmaniasis are costly, toxic, with multiple side effects, and limitations in the administration route. The rapid emergence of drug resistance has severely reduced the potency of anti-leishmanial drugs. As a result, there is a pressing need for the development of novel anti-leishmanial drugs with high potency, low cost, acceptable toxicity, and good pharmacokinetics features. Due to the availability of preclinical data, drug repurposing is a valuable approach for speeding up the development of effective anti-leishmanial through pointing to new drug targets in less time, having low costs and risk. Metabolic pathways of this parasite play a crucial role in the growth and proliferation of Leishmania species during the various stages of their life cycle. Based on available genomics/proteomics information, known pathways-based (sterol biosynthetic pathway, purine salvage pathway, glycolysis, GPI biosynthesis, hypusine, polyamine biosynthesis) Leishmania-specific proteins could be targeted with known drugs that were used in other diseases, resulting in finding new promising anti-leishmanial therapeutics. The present review discusses various metabolic pathways of the Leishmania parasite and some drug candidates targeting these pathways effectively that could be potent drugs against leishmaniasis in the future.

show abstract

Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents

Cited by 10 publications

References 44 publications

Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents

Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents

Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective

Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

Contact Info

Product

Resources

About