Intrinsic fluorescence properties of antimalarial pyrido[1,2-<i>a</i>]benzimidazoles facilitate subcellular accumulation and mechanistic studies in the human malaria parasite <i>Plasmodium falciparum</i>

Korkor, Constance M.; Garnie, Larnelle F.; Amod, Leah; Egan, Timothy J.; Chibale, Kelly

doi:10.1039/d0ob01730b

Cited by 10 publications

(12 citation statements)

References 48 publications

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“…For example, intracellular colocalization studies performed on PBI.1, which has ABS activity (Supporting Information) showed cytoplasmic accumulation without any hemozoin inhibition, in contrast to the closely related congener PBI.2. 27 However, the possibility of a shared target between ABS and late-stage gametocytes cannot be excluded, but these results suggest that within the PBI chemical series different mechanistic actions are at play; thus, to a large extent analogues must be considered on their own merit. Additionally, it is unlikely that uptake differences can explain this phenomena since these two compounds do not show marked physical differences compared to other close analogues (e.g., PBI.103).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…This lack of activity against early stage gametocytes is not easily explained due to different biological targets since the mode(s) of action (MoA) of the PBIs in any Plasmodium life cycle stage remains uncertain. For example, intracellular colocalization studies performed on PBI.1 , which has ABS activity (Supporting Information) showed cytoplasmic accumulation without any hemozoin inhibition, in contrast to the closely related congener PBI.2 . However, the possibility of a shared target between ABS and late-stage gametocytes cannot be excluded, but these results suggest that within the PBI chemical series different mechanistic actions are at play; thus, to a large extent analogues must be considered on their own merit.…”

Section: Resultsmentioning

confidence: 99%

“…Heme detoxification is an essential process for parasite survival particularly during ABS, and its disruption leads to parasite death . In fact, the first-generation B-I series and some PBIs , are true inhibitors of hemozoin formation as demonstrated in a cell-based assay. Although not critical to early stage gametocytes, heme degradation is present in the earlier stages of development but not in late-stage gametocytes .…”

Section: Resultsmentioning

confidence: 99%

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Benzimidazole Derivatives Are Potent against Multiple Life Cycle Stages of Plasmodium falciparum Malaria Parasites

et al. 2021

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The continued emergence of resistance to front-line antimalarial treatments is of great concern. Therefore, new compounds that potentially have a novel target in various developmental stages of Plasmodium parasites are needed to treat patients and halt the spread of malaria. Here, several benzimidazole derivatives were screened for activity against the symptom-causing intraerythrocytic asexual blood stages and the transmissible gametocyte stages of P. falciparum. Submicromolar activity was obtained for 54 compounds against asexual blood stage parasites with 6 potent at IC50 < 100 nM while not displaying any marked toxicity against mammalian cells. Nanomolar potency was also observed against gametocytes with two compounds active against early stage gametocytes and two compounds active against late-stage gametocytes. The transmission-blocking potential of the latter was confirmed as they could prevent male gamete exflagellation and the lead compound reduced transmission by 72% in an in vivo mosquito feeding model. These compounds therefore have activity against multiple stages of Plasmodium parasites with potential for differential targets.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Benzimidazole Derivatives Are Potent against Multiple Life Cycle Stages of Plasmodium falciparum Malaria Parasites

et al. 2021

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“…Recently, Korkor et al. applied antimalarial pyrido[1,2‐a]benzimidazoles (PBI) and investigated the localization of the compounds within P. falciparum [142] . Another example can be made of one of the most fascinating antimalaria drugs, methylene blue (Figure 11a).…”

Section: Chemical Biology Tools In Plasmodium Falciparum Researchmentioning

confidence: 99%

“…applied antimalarial pyrido[1,2‐a]benzimidazoles (PBI) and investigated the localization of the compounds within P. falciparum . [142] Another example can be made of one of the most fascinating antimalaria drugs, methylene blue (Figure 11 a). Discovered by Caro in the late 19th century, it was used in malaria treatment by Ehrlich at the beginning of the 20th century.…”

Section: Chemical Biology Tools In Plasmodium Falciparum Researchmentioning

confidence: 99%

Chemical Biology Tools To Investigate Malaria Parasites

Broichhagen

Kilian

2021

ChemBioChem

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Parasitic diseases like malaria tropica have been shaping human evolution and history since the beginning of mankind. After infection, the response of the human host ranges from asymptomatic to severe and may culminate in death. Therefore, proper examination of the parasite's biology is pivotal to deciphering unique molecular, biochemical and cell biological processes, which in turn ensure the identification of treatment strategies, such as potent drug targets and vaccine candidates. However, implementing molecular biology methods for genetic manipulation proves to be difficult for many parasite model organisms. The development of fast and straightforward applicable alternatives, for instance small‐molecule probes from the field of chemical biology, is essential. In this review, we will recapitulate the highlights of previous molecular and chemical biology approaches that have already created insight and understanding of the malaria parasite Plasmodium falciparum. We discuss current developments from the field of chemical biology and explore how their application could advance research into this parasite in the future. We anticipate that the described approaches will help to close knowledge gaps in the biology of P. falciparum and we hope that researchers will be inspired to use these methods to gain knowledge – with the aim of ending this devastating disease.

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Synthesis and Exploration of New Imidazo[4,5‐c]Pyrazoles as Potent α‐Amylase Inhibitors

et al. 2023

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To identify new leads of small molecules as α‐amylase inhibitors, the current research is focused on the assessment of imidazopyrazoles. Hence, a set of novel imidazo[4,5‐c]pyrazoles was synthesized via simple versatile straightforward synthetic routes and was estimated for their in vitro α‐amylase inhibition activity. The findings revealed that diphenylaminomethyl and phenylcarbamodithioate derivatives elicited potent α‐amylase inhibition activities with IC50 values of 0.071 and 0.083 μM, respectively that were comparable to acarbose (IC50 0.060 μM). Molecular docking and in silico studies were performed for the most active derivatives and demonstrated that docked compounds have good binding affinities toward α‐amylase with binding free energies that are very similar to that of acarbose. Furthermore, these compounds demonstrated not only significant biological activity but also noteworthy physicochemical properties, drug‐likeness, and good pharmacokinetics. As a result, such compounds offered a robust opportunity for further development and optimization of the imidazopyrazole scaffold for the potential management of Type II Diabetes Mellitus.

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Intrinsic fluorescence properties of antimalarial pyrido[1,2-a]benzimidazoles facilitate subcellular accumulation and mechanistic studies in the human malaria parasite Plasmodium falciparum

Abstract: The intrinsic fluorescence properties of two related pyrido[1,2-a]benzimidazole antimalarial compounds suitable for cellular imaging of the human malaria parasite Plasmodium falciparum without the need to attach extrinsic fluorophores are described....

Cited by 10 publications

References 48 publications

Benzimidazole Derivatives Are Potent against Multiple Life Cycle Stages of Plasmodium falciparum Malaria Parasites

Benzimidazole Derivatives Are Potent against Multiple Life Cycle Stages of Plasmodium falciparum Malaria Parasites

Chemical Biology Tools To Investigate Malaria Parasites

Synthesis and Exploration of New Imidazo[4,5‐c]Pyrazoles as Potent α‐Amylase Inhibitors

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