Unsymmetrical Bisquinolines with High Potency against P. falciparum Malaria

Liebman, Katherine May; Burgess, Steven J.; Gunsaru, Bornface; Kelly, Jane X.; Li, Yuexin; Morrill, Westin; Liebman, Michael C.; Peyton, David H.

doi:10.3390/molecules25092251

Cited by 11 publications

(18 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Third, consider chloroquine, an antimalarial drug, and DM1157 a novel reversed chloroquine compound consisting of a chloroquine backbone with an attached reversal agent (Generous gift from Professor David Peyton and Dr. Katherine Liebman, Portland State University). 25–27 Unlike the DOTA and DO3A examples above, chloroquine and DM1157 displayed essentially identical thermodynamic contributions of binding to HSA thermodynamic stability, i.e. Δ H B = ~ 60 kcal/mol, Δ G B = ~ 5 kcal/mol, and Δ T m = ~ 1°C for both compounds.…”

Section: Resultsmentioning

confidence: 93%

See 1 more Smart Citation

Evaluation of Drug/Ligand Binding Constants for Human Serum Albumin Using Differential Scanning Calorimetry

2021

Preprint

View full text Add to dashboard Cite

This paper reports utilization of differential scanning calorimetry measurements to evaluate binding constants for Human Serum Albumin of 28 different drug ligands. Protein/ligand mixtures were prepared at various ligand concentrations and subjected to thermal denaturation analysis by calorimetry. From the measurements, the melting temperature, Tm, and free-energy ΔGcal(37°C) for melting ligand-bound Albumin were evaluated as a function of ligand concentration. Concentration dependent behaviors of ΔGcal(37°C) and Tm derived from protein/ligand mixtures were used to construct dose-response curves. Model fits of dose-response curves yielded quantitative evaluation of the ligand binding constant, KD, and semi-quantitative estimates of the binding stoichiometry, n. Many of the ligands had known binding affinity for Albumin with binding constants reported in the literature. Evaluated Albumin binding parameters for the ligands impressively agreed with reported literature values determined using other standard experimental methods. These results demonstrated utility of our calorimetry-based process for applications in pre-clinical drug screening.

show abstract

Section: Resultsmentioning

confidence: 93%

“…Gadavist (GAD) and Magnevist (MAG) were purchased from Bayer (Leverkusen, Germany); Dotarem (DOT) from Guerbet (Villepinte, France); Ablavar (AB) from Lantheus Medical Imaging (Billerica, MA); and Δ9-tetrahydrocanabinol (THC) from Cerilliant (Round Rock, TX). The novel compound DM1157 [25][26][27]…”

Section: -24mentioning

confidence: 99%

Evaluation of Drug/Ligand Binding Constants for Human Serum Albumin Using Differential Scanning Calorimetry

2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Consequently, the antimalarial literature is replete with quinoline and related heterocyclic molecules . Additionally, several hybrid molecules , and bisquinoline molecules − are reported to possess potent antiplasmodial activity. The former consists of 4-aminoquinoline pharmacophore in conjunction with other heterocycles, while the latter contains two quinoline rings (total four #Ar) attached with a variable linker.…”

Section: Resultsmentioning

confidence: 99%

Physicochemical Profiling and Comparison of Research Antiplasmodials and Advanced Stage Antimalarials with Oral Drugs

Bhanot

Sundriyal

2021

ACS Omega

View full text Add to dashboard Cite

To understand the property space of antimalarials, we collated a large dataset of research antiplasmodial (RAP) molecules with known in vitro potencies and advanced stage antimalarials (ASAMs) with established oral bioavailability. While RAP molecules are “non-druglike”, ASAM molecules display properties closer to Lipinski’s and Veber’s thresholds. Comparison within the different potency groups of RAP molecules indicates that the in vitro potency is positively correlated to the molecular weight, the calculated octanol–water partition coefficient (clog P), aromatic ring counts (#Ar), and hydrogen bond acceptors. Despite both categories being bioavailable, the ASAM molecules are relatively larger and more lipophilic, have a lower polar surface area, and possess a higher count of heteroaromatic rings than oral drugs. Also, antimalarials are found to have a higher proportion of aromatic (#ArN) and basic nitrogen (#BaN) counts, features implicitly used in the design of antimalarial molecules but not well studied hitherto. We also propose using descriptors scaled by the sum of #ArN and #BaN (SBAN) to define an antimalarial property space. Together, these results may have important applications in the identification and optimization of future antimalarials.

show abstract

“…Despite the emergence of resistance to 4-aminoquinoline drugs, this pharmacophore has a crucial role inhibiting the heme polymerization and parasite growing. It is believed that the steric hindrance in bulky compounds, such as bisquinolines, would avoid the drug efflux and overcome the resistance [ 35 , 36 , 37 ]. However, hybrids containing the acridine and quinoline moieties are scarcely reported.…”

Section: Hybrids Containing the 9-aminoacridine Scaffoldmentioning

confidence: 99%

Acridine-Based Antimalarials—From the Very First Synthetic Antimalarial to Recent Developments

et al. 2021

View full text Add to dashboard Cite

Malaria is among the deadliest infectious diseases in the world caused by Plasmodium parasites. Due to the high complexity of the parasite’s life cycle, we partly depend on antimalarial drugs to fight this disease. However, the emergence of resistance, mainly by Plasmodium falciparum, has dethroned most of the antimalarials developed to date. Given recent reports of resistance to artemisinin combination therapies, first-line treatment currently recommended by the World Health Organization, in Western Cambodia and across the Greater Mekong sub-region, it seems very likely that artemisinin and its derivatives will follow the same path of other antimalarial drugs. Consequently, novel, safe and efficient antimalarial drugs are urgently needed. One fast and low-cost strategy to accelerate antimalarial development is by recycling classical pharmacophores. Quinacrine, an acridine-based compound and the first clinically tested synthetic antimalarial drug with potent blood schizonticide but serious side effects, has attracted attention due to its broad spectrum of biological activity. In this sense, the present review will focus on efforts made in the last 20 years for the development of more efficient, safer and affordable antimalarial compounds, through recycling the classical quinacrine drug.

show abstract

Unsymmetrical Bisquinolines with High Potency against P. falciparum Malaria

Cited by 11 publications

References 70 publications

Evaluation of Drug/Ligand Binding Constants for Human Serum Albumin Using Differential Scanning Calorimetry

Evaluation of Drug/Ligand Binding Constants for Human Serum Albumin Using Differential Scanning Calorimetry

Physicochemical Profiling and Comparison of Research Antiplasmodials and Advanced Stage Antimalarials with Oral Drugs

Acridine-Based Antimalarials—From the Very First Synthetic Antimalarial to Recent Developments

Contact Info

Product

Resources

About