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Colin W. Wright - One of the best experts on this subject based on the ideXlab platform.

  • recent advances in the chemistry and pharmacology of Cryptolepine
    Progress in the chemistry of organic natural products, 2021
    Co-Authors: Steven D Shnyder, Colin W. Wright
    Abstract:

    Cryptolepine, the principal constituent of the West African climbing shrub Cryptolepis sanguinolenta, continues to be of interest as a lead to new therapeutic agents, especially for the treatment of protozoal infections and cancer. This contribution reviews the research published in the last decade, highlighting new synthesis routes to Cryptolepine and to analogs of this alkaloid, as well as their pharmacology. Studies relating to the use of C. sanguinolenta as an herbal medicine for the treatment of malaria are discussed, as well as the development of analogs of Cryptolepine as leads to new agents for the treatment of malaria, trypanosomiasis, and cancer with an emphasis on the pharmacological mechanisms involved. Other potential therapeutic applications include antimicrobial, antidiabetic, and anti-inflammatory activities; the pharmacokinetics and toxicity of Cryptolepine are also reviewed.

  • in vitro anti malarial interaction and gametocytocidal activity of Cryptolepine
    Malaria Journal, 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Kwesi Boadu Mensah, Kofi Annan, Ben Gyan, Anjo Theron, Dalu Mancama, Colin W. Wright
    Abstract:

    Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, Cryptolepine. This study also investigates the anti-malarial interaction of Cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues. The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and Cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of Cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7. Cryptolepis sanguinolenta (IC50 = 49.65 nM) and its major alkaloid, Cryptolepine (IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, Cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine. The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and Cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for Cryptolepine in the development of novel fixed dose combinations.

  • identification of Cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of Cryptolepine in sprague dawley rats
    BMC Clinical Pharmacology, 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Colin W. Wright, David Pearson, Werner Gertsch, Amanda L Cirello, Adam Amaral, Jaimie Spear, Caroline Rynn
    Abstract:

    This study aims at characterizing the in vitro metabolism of Cryptolepine using human and rat hepatocytes, identifying metabolites in rat plasma and urine after a single Cryptolepine dose, and evaluating the single-dose oral and intravenous pharmacokinetics of Cryptolepine in male Sprague Dawley (SD) rats. The in vitro metabolic profiles of Cryptolepine were determined by LC-MS/MS following incubation with rat and human hepatocytes. The in vivo metabolic profile of Cryptolepine was determined in plasma and urine samples from Sprague Dawley rats following single-dose oral administration of Cryptolepine. Pharmacokinetic parameters of Cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose intravenous and oral administration. Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine and plasma of rats following oral administration of Cryptolepine. Unchanged Cryptolepine detected in urine was negligible. The Pharmacokinetic profile of Cryptolepine showed a very high plasma clearance and volume of distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma exposure and oral bioavailability were low. Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive distribution with a moderate half-life.

  • In vitro anti-malarial interaction and gametocytocidal activity of Cryptolepine
    'Springer Science and Business Media LLC', 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Kwesi Boadu Mensah, Kofi Annan, Ben Gyan, Anjo Theron, Dalu Mancama, Colin W. Wright
    Abstract:

    Abstract Background Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, Cryptolepine. This study also investigates the anti-malarial interaction of Cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues. Methods The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and Cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of Cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7. Results Cryptolepis sanguinolenta (IC50 = 49.65 nM) and its major alkaloid, Cryptolepine (IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, Cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine. Conclusions The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and Cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for Cryptolepine in the development of novel fixed dose combinations

  • Identification of Cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of Cryptolepine in Sprague Dawley rats
    'Springer Science and Business Media LLC', 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Colin W. Wright, David Pearson, Werner Gertsch, Amanda L Cirello, Adam Amaral, Jaimie Spear, Caroline Rynn
    Abstract:

    Abstract Background This study aims at characterizing the in vitro metabolism of Cryptolepine using human and rat hepatocytes, identifying metabolites in rat plasma and urine after a single Cryptolepine dose, and evaluating the single-dose oral and intravenous pharmacokinetics of Cryptolepine in male Sprague Dawley (SD) rats. Methods The in vitro metabolic profiles of Cryptolepine were determined by LC-MS/MS following incubation with rat and human hepatocytes. The in vivo metabolic profile of Cryptolepine was determined in plasma and urine samples from Sprague Dawley rats following single-dose oral administration of Cryptolepine. Pharmacokinetic parameters of Cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose intravenous and oral administration. Results Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine and plasma of rats following oral administration of Cryptolepine. Unchanged Cryptolepine detected in urine was negligible. The Pharmacokinetic profile of Cryptolepine showed a very high plasma clearance and volume of distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma exposure and oral bioavailability were low. Conclusions Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive distribution with a moderate half-life

Charles Ansah - One of the best experts on this subject based on the ideXlab platform.

  • Cryptolepine inhibits hepatocellular carcinoma growth through inhibiting interleukin 6 stat3 signalling
    BMC Complementary Medicine and Therapies, 2021
    Co-Authors: Seth A Domfeh, Charles Ansah, Patrick Williams Narkwa, Osbourne Quaye, Kwadwo A Kusi, Gordon A Awandare, Alimatu Salam, Mohamed Mutocheluh
    Abstract:

    Diverse signalling pathways are involved in carcinogenesis and one of such pathways implicated in many cancers is the interleukin 6/signal transducer and activator of transcription 3 (IL-6/STAT3) signalling pathway. Therefore, inhibition of this pathway is targeted as an anti-cancer intervention. This study aimed to establish the effect of Cryptolepine, which is the main bioactive alkaloid in the medicinal plant Cryptolepis sanguinolenta, on the IL-6/STAT3 signalling pathway. First, the effect of Cryptolepine on the IL-6/STAT3 pathway in human hepatoma cells (HepG2 cells) was screened using the Cignal Finder Multi-Pathway Reporter Array. Next, to confirm the effect of Cryptolepine on the IL-6/STAT3 signalling pathway, the pathway was activated using 200 ng/mL IL-6 in the presence of 0.5–2 μM Cryptolepine. The levels of total STAT3, p-STAT3 and IL-23 were assessed by ELISA. Cryptolepine downregulated 12 signalling pathways including the IL-6/STAT3 signalling pathway and upregulated 17 signalling pathways. Cryptolepine, in the presence of IL-6, decreased the levels of p-STAT3 and IL-23 in a dose-dependent fashion. Our results demonstrated that Cryptolepine inhibits the IL-6/STAT3 signalling pathway, and therefore Cryptolepine-based remedies such as Cryptolepis sanguinolenta could potentially be used as an effective immunotherapeutic agent for hepatocellular carcinoma and other cancers.

  • Cryptolepine the major alkaloid of cryptolepis sanguinolenta lindl schlechter apocynaceae attenuates early and late phase symptoms of asthma
    Scientific African, 2020
    Co-Authors: Paapa Mensahkane, Kwesi Boadu Mensah, Aaron Opoku Antwi, Arnold Donkor Forkuo, Charles Ansah
    Abstract:

    Abstract Aqueous root extract of Cryptolepis sanguinolenta has been used traditionally to treat many upper respiratory tract disorders. Besides its well-known broad spectrum antimicrobial activity, we had reasoned that Cryptolepine can directly attenuate the symptoms of asthma. Therefore, this study evaluates Cryptolepine, the main compound of the aqueous extract of Cryptolepis sanguinolenta, on early and late-phase symptoms of asthma attack. In the early phase study, isolated Cryptolepine was evaluated on its ability to reverse histamine-induced bronchoconstriction and reduce histamine release from mast cells and bronchial mucus secretion. In the late phase study, Cryptolepine was evaluated on its ability to affect airway inflammation and hypersensitivity as well as its ability to attenuate airway remodeling induced by ovalbumin. In the early asthma phase study, Cryptolepine (10–100 mg/kg) significantly and dose dependently inhibited Histamine-induced bronchoconstriction in guinea pigs. The protection lasted beyond 24 h. It also decreased the volume and optical density of bronchial secretions in mice. Cryptolepine (10–100 µg /mL) stabilized mesentery mast cells in vitro against Compound 48/80 -induced degranulation. In the late phase study, Cryptolepine (10–100 mg/kg) prevented ovalbumin-induced airway obstruction and basal membrane smooth muscle hypertrophy. It significantly reduced systemic leukocytosis and inflammatory cell infiltration into airways in antigen-sensitized animals. Using the skin prick test, Cryptolepine reduced the hypersensitivity to allergen challenge in antigen-sensitized animals. Cryptolepine's effects in the late phase was similar to dexamethasone (1 mg/kg) used as standard drug. Cryptolepine attenuates both early and late phase symptoms of asthma. It reduces bronchospasms, bronchial secretions, airway remodeling and hypersensitivity. This gives scientific credence to the traditional usage of cryptolepis extracts in upper respiratory tract disorders.

  • Cryptolepine the main alkaloid of the antimalarial cryptolepis sanguinolenta lindl schlechter induces malformations in zebrafish embryos
    Biochemistry Research International, 2019
    Co-Authors: Kwesi Boadu Mensah, Arnold Donkor Forkuo, Charles Kwaku Benneh, Charles Ansah
    Abstract:

    Background. Previous studies on Cryptolepine, the antimalarial and cytotoxic alkaloid of Cryptolepis sanguinolenta, showed that it preferentially accumulates in rapidly proliferating cells and melanin-containing tissues. Subsequently, we demonstrated that Cryptolepine was toxic to murine embryos in vivo but no signs of teratogenicity. in vivo developmental studies can be confounded by maternal effects. Here, we hypothesized that Cryptolepine-induced embryo toxicity occurs at least partly through direct inhibition of embryogenesis rather than indirectly through the induction of maternal toxicity. Aim. To determine the effects of Cryptolepine on developing zebrafish embryos ex vivo. Methods. Healthy synchronized zebrafish eggs were treated with Cryptolepine (10−1 − 5 × 102 μM), benzyl penicillin (6 − 6 × 102 μM), or mercury chloride (3.7 × 10−1 − 3.7 × 101 nM) from 6 to 72 hours postfertilization. Developing embryos were assessed at 24, 48, 72, and 96 hours under microscope for lethality, hatching rate, and malformation. Results. LC50 for Cryptolepine in the study was found to be 260 ± 0.174 μM. Cryptolepine induced dose- and time-dependent mortality from the 24 to 96 hours postfertilization. Lower Cryptolepine concentration (<100 μM) caused mortality, approximately 15–18%, only after the 48 hours postfertilization. The most sensitive period of embryo lethality corresponded well with the pharyngula (24 to 48 hours) and hatching (48 to 72 hours) stages of embryonic development. Cryptolepine (10−1 − 5 × 102 μM) dose dependently inhibited the hatching rate. At doses above 500 μM, hatching was completely inhibited. Mercury chloride (3.7 × 10−1 − 3.7 × 101 nM), used as positive control, induced a consistent pattern of embryo lethality at all stages of development, whereas benzyl penicillin (6 − 6 × 102 μM), used as negative control, did not induce any significant embryo lethality. Morphological examination of (postfertilization day 5) of eleutheroembryos treated during embryonic development with Cryptolepine showed decreased body length (growth inhibition), decreased eye diameter and bulginess, enlarged pericardia, and enlarged yolk sac and muscle malformations. Conclusion. Cryptolepine induces malformations, growth retardation, and mortalities in rapidly dividing zebrafish embryos ex vivo.

  • in vitro anti malarial interaction and gametocytocidal activity of Cryptolepine
    Malaria Journal, 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Kwesi Boadu Mensah, Kofi Annan, Ben Gyan, Anjo Theron, Dalu Mancama, Colin W. Wright
    Abstract:

    Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, Cryptolepine. This study also investigates the anti-malarial interaction of Cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues. The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and Cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of Cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7. Cryptolepis sanguinolenta (IC50 = 49.65 nM) and its major alkaloid, Cryptolepine (IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, Cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine. The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and Cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for Cryptolepine in the development of novel fixed dose combinations.

  • identification of Cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of Cryptolepine in sprague dawley rats
    BMC Clinical Pharmacology, 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Colin W. Wright, David Pearson, Werner Gertsch, Amanda L Cirello, Adam Amaral, Jaimie Spear, Caroline Rynn
    Abstract:

    This study aims at characterizing the in vitro metabolism of Cryptolepine using human and rat hepatocytes, identifying metabolites in rat plasma and urine after a single Cryptolepine dose, and evaluating the single-dose oral and intravenous pharmacokinetics of Cryptolepine in male Sprague Dawley (SD) rats. The in vitro metabolic profiles of Cryptolepine were determined by LC-MS/MS following incubation with rat and human hepatocytes. The in vivo metabolic profile of Cryptolepine was determined in plasma and urine samples from Sprague Dawley rats following single-dose oral administration of Cryptolepine. Pharmacokinetic parameters of Cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose intravenous and oral administration. Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine and plasma of rats following oral administration of Cryptolepine. Unchanged Cryptolepine detected in urine was negligible. The Pharmacokinetic profile of Cryptolepine showed a very high plasma clearance and volume of distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma exposure and oral bioavailability were low. Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive distribution with a moderate half-life.

Kwesi Boadu Mensah - One of the best experts on this subject based on the ideXlab platform.

  • Cryptolepine the major alkaloid of cryptolepis sanguinolenta lindl schlechter apocynaceae attenuates early and late phase symptoms of asthma
    Scientific African, 2020
    Co-Authors: Paapa Mensahkane, Kwesi Boadu Mensah, Aaron Opoku Antwi, Arnold Donkor Forkuo, Charles Ansah
    Abstract:

    Abstract Aqueous root extract of Cryptolepis sanguinolenta has been used traditionally to treat many upper respiratory tract disorders. Besides its well-known broad spectrum antimicrobial activity, we had reasoned that Cryptolepine can directly attenuate the symptoms of asthma. Therefore, this study evaluates Cryptolepine, the main compound of the aqueous extract of Cryptolepis sanguinolenta, on early and late-phase symptoms of asthma attack. In the early phase study, isolated Cryptolepine was evaluated on its ability to reverse histamine-induced bronchoconstriction and reduce histamine release from mast cells and bronchial mucus secretion. In the late phase study, Cryptolepine was evaluated on its ability to affect airway inflammation and hypersensitivity as well as its ability to attenuate airway remodeling induced by ovalbumin. In the early asthma phase study, Cryptolepine (10–100 mg/kg) significantly and dose dependently inhibited Histamine-induced bronchoconstriction in guinea pigs. The protection lasted beyond 24 h. It also decreased the volume and optical density of bronchial secretions in mice. Cryptolepine (10–100 µg /mL) stabilized mesentery mast cells in vitro against Compound 48/80 -induced degranulation. In the late phase study, Cryptolepine (10–100 mg/kg) prevented ovalbumin-induced airway obstruction and basal membrane smooth muscle hypertrophy. It significantly reduced systemic leukocytosis and inflammatory cell infiltration into airways in antigen-sensitized animals. Using the skin prick test, Cryptolepine reduced the hypersensitivity to allergen challenge in antigen-sensitized animals. Cryptolepine's effects in the late phase was similar to dexamethasone (1 mg/kg) used as standard drug. Cryptolepine attenuates both early and late phase symptoms of asthma. It reduces bronchospasms, bronchial secretions, airway remodeling and hypersensitivity. This gives scientific credence to the traditional usage of cryptolepis extracts in upper respiratory tract disorders.

  • Cryptolepine the main alkaloid of the antimalarial cryptolepis sanguinolenta lindl schlechter induces malformations in zebrafish embryos
    Biochemistry Research International, 2019
    Co-Authors: Kwesi Boadu Mensah, Arnold Donkor Forkuo, Charles Kwaku Benneh, Charles Ansah
    Abstract:

    Background. Previous studies on Cryptolepine, the antimalarial and cytotoxic alkaloid of Cryptolepis sanguinolenta, showed that it preferentially accumulates in rapidly proliferating cells and melanin-containing tissues. Subsequently, we demonstrated that Cryptolepine was toxic to murine embryos in vivo but no signs of teratogenicity. in vivo developmental studies can be confounded by maternal effects. Here, we hypothesized that Cryptolepine-induced embryo toxicity occurs at least partly through direct inhibition of embryogenesis rather than indirectly through the induction of maternal toxicity. Aim. To determine the effects of Cryptolepine on developing zebrafish embryos ex vivo. Methods. Healthy synchronized zebrafish eggs were treated with Cryptolepine (10−1 − 5 × 102 μM), benzyl penicillin (6 − 6 × 102 μM), or mercury chloride (3.7 × 10−1 − 3.7 × 101 nM) from 6 to 72 hours postfertilization. Developing embryos were assessed at 24, 48, 72, and 96 hours under microscope for lethality, hatching rate, and malformation. Results. LC50 for Cryptolepine in the study was found to be 260 ± 0.174 μM. Cryptolepine induced dose- and time-dependent mortality from the 24 to 96 hours postfertilization. Lower Cryptolepine concentration (<100 μM) caused mortality, approximately 15–18%, only after the 48 hours postfertilization. The most sensitive period of embryo lethality corresponded well with the pharyngula (24 to 48 hours) and hatching (48 to 72 hours) stages of embryonic development. Cryptolepine (10−1 − 5 × 102 μM) dose dependently inhibited the hatching rate. At doses above 500 μM, hatching was completely inhibited. Mercury chloride (3.7 × 10−1 − 3.7 × 101 nM), used as positive control, induced a consistent pattern of embryo lethality at all stages of development, whereas benzyl penicillin (6 − 6 × 102 μM), used as negative control, did not induce any significant embryo lethality. Morphological examination of (postfertilization day 5) of eleutheroembryos treated during embryonic development with Cryptolepine showed decreased body length (growth inhibition), decreased eye diameter and bulginess, enlarged pericardia, and enlarged yolk sac and muscle malformations. Conclusion. Cryptolepine induces malformations, growth retardation, and mortalities in rapidly dividing zebrafish embryos ex vivo.

  • in vitro anti malarial interaction and gametocytocidal activity of Cryptolepine
    Malaria Journal, 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Kwesi Boadu Mensah, Kofi Annan, Ben Gyan, Anjo Theron, Dalu Mancama, Colin W. Wright
    Abstract:

    Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, Cryptolepine. This study also investigates the anti-malarial interaction of Cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues. The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and Cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of Cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7. Cryptolepis sanguinolenta (IC50 = 49.65 nM) and its major alkaloid, Cryptolepine (IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, Cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine. The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and Cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for Cryptolepine in the development of novel fixed dose combinations.

  • In vitro anti-malarial interaction and gametocytocidal activity of Cryptolepine
    'Springer Science and Business Media LLC', 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Kwesi Boadu Mensah, Kofi Annan, Ben Gyan, Anjo Theron, Dalu Mancama, Colin W. Wright
    Abstract:

    Abstract Background Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, Cryptolepine. This study also investigates the anti-malarial interaction of Cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues. Methods The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and Cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of Cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7. Results Cryptolepis sanguinolenta (IC50 = 49.65 nM) and its major alkaloid, Cryptolepine (IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, Cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine. Conclusions The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and Cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for Cryptolepine in the development of novel fixed dose combinations

  • a review of the anticancer potential of the antimalarial herbal cryptolepis sanguinolenta and its major alkaloid Cryptolepine
    Ghana Medical Journal, 2013
    Co-Authors: Charles Ansah, Kwesi Boadu Mensah
    Abstract:

    Cryptolepis sanguinolenta (Lindl.) Schltr (Periplocaceae), has a longstanding traditional use in the treatment of malaria in the West African region. Recent evidence suggests that the aqueous extract from the roots and the major alkaloid from the plant, Cryptolepine, have prospects as cancer chemotherapeutic agents on account of their potent cytotoxicity to mammalian cells. Several mechanisms have been proposed to explain the cytotoxic activities of the agents. However, emerging evidence from their anti-inflammatory actions suggest that the mechanism of the cytotoxicity may be closely related to its antiinflammatory activity. This review looks at the mechanisms of cryptolepis-induced cytotoxicity, its link with inflammation and its potential as anticancer agent. The elucidation of these interwoven mechanisms may be useful in the development of Cryptolepine or other analogues as new anticancer agents.

Arnold Donkor Forkuo - One of the best experts on this subject based on the ideXlab platform.

  • Cryptolepine the major alkaloid of cryptolepis sanguinolenta lindl schlechter apocynaceae attenuates early and late phase symptoms of asthma
    Scientific African, 2020
    Co-Authors: Paapa Mensahkane, Kwesi Boadu Mensah, Aaron Opoku Antwi, Arnold Donkor Forkuo, Charles Ansah
    Abstract:

    Abstract Aqueous root extract of Cryptolepis sanguinolenta has been used traditionally to treat many upper respiratory tract disorders. Besides its well-known broad spectrum antimicrobial activity, we had reasoned that Cryptolepine can directly attenuate the symptoms of asthma. Therefore, this study evaluates Cryptolepine, the main compound of the aqueous extract of Cryptolepis sanguinolenta, on early and late-phase symptoms of asthma attack. In the early phase study, isolated Cryptolepine was evaluated on its ability to reverse histamine-induced bronchoconstriction and reduce histamine release from mast cells and bronchial mucus secretion. In the late phase study, Cryptolepine was evaluated on its ability to affect airway inflammation and hypersensitivity as well as its ability to attenuate airway remodeling induced by ovalbumin. In the early asthma phase study, Cryptolepine (10–100 mg/kg) significantly and dose dependently inhibited Histamine-induced bronchoconstriction in guinea pigs. The protection lasted beyond 24 h. It also decreased the volume and optical density of bronchial secretions in mice. Cryptolepine (10–100 µg /mL) stabilized mesentery mast cells in vitro against Compound 48/80 -induced degranulation. In the late phase study, Cryptolepine (10–100 mg/kg) prevented ovalbumin-induced airway obstruction and basal membrane smooth muscle hypertrophy. It significantly reduced systemic leukocytosis and inflammatory cell infiltration into airways in antigen-sensitized animals. Using the skin prick test, Cryptolepine reduced the hypersensitivity to allergen challenge in antigen-sensitized animals. Cryptolepine's effects in the late phase was similar to dexamethasone (1 mg/kg) used as standard drug. Cryptolepine attenuates both early and late phase symptoms of asthma. It reduces bronchospasms, bronchial secretions, airway remodeling and hypersensitivity. This gives scientific credence to the traditional usage of cryptolepis extracts in upper respiratory tract disorders.

  • Cryptolepine the main alkaloid of the antimalarial cryptolepis sanguinolenta lindl schlechter induces malformations in zebrafish embryos
    Biochemistry Research International, 2019
    Co-Authors: Kwesi Boadu Mensah, Arnold Donkor Forkuo, Charles Kwaku Benneh, Charles Ansah
    Abstract:

    Background. Previous studies on Cryptolepine, the antimalarial and cytotoxic alkaloid of Cryptolepis sanguinolenta, showed that it preferentially accumulates in rapidly proliferating cells and melanin-containing tissues. Subsequently, we demonstrated that Cryptolepine was toxic to murine embryos in vivo but no signs of teratogenicity. in vivo developmental studies can be confounded by maternal effects. Here, we hypothesized that Cryptolepine-induced embryo toxicity occurs at least partly through direct inhibition of embryogenesis rather than indirectly through the induction of maternal toxicity. Aim. To determine the effects of Cryptolepine on developing zebrafish embryos ex vivo. Methods. Healthy synchronized zebrafish eggs were treated with Cryptolepine (10−1 − 5 × 102 μM), benzyl penicillin (6 − 6 × 102 μM), or mercury chloride (3.7 × 10−1 − 3.7 × 101 nM) from 6 to 72 hours postfertilization. Developing embryos were assessed at 24, 48, 72, and 96 hours under microscope for lethality, hatching rate, and malformation. Results. LC50 for Cryptolepine in the study was found to be 260 ± 0.174 μM. Cryptolepine induced dose- and time-dependent mortality from the 24 to 96 hours postfertilization. Lower Cryptolepine concentration (<100 μM) caused mortality, approximately 15–18%, only after the 48 hours postfertilization. The most sensitive period of embryo lethality corresponded well with the pharyngula (24 to 48 hours) and hatching (48 to 72 hours) stages of embryonic development. Cryptolepine (10−1 − 5 × 102 μM) dose dependently inhibited the hatching rate. At doses above 500 μM, hatching was completely inhibited. Mercury chloride (3.7 × 10−1 − 3.7 × 101 nM), used as positive control, induced a consistent pattern of embryo lethality at all stages of development, whereas benzyl penicillin (6 − 6 × 102 μM), used as negative control, did not induce any significant embryo lethality. Morphological examination of (postfertilization day 5) of eleutheroembryos treated during embryonic development with Cryptolepine showed decreased body length (growth inhibition), decreased eye diameter and bulginess, enlarged pericardia, and enlarged yolk sac and muscle malformations. Conclusion. Cryptolepine induces malformations, growth retardation, and mortalities in rapidly dividing zebrafish embryos ex vivo.

  • isobolographic analysis of co administration of two plant derived antiplasmodial drug candidates Cryptolepine and xylopic acid in plasmodium berghei
    Malaria Journal, 2018
    Co-Authors: Elvis Ofori Ameyaw, Kodwo B Asmah, Robert Peter Biney, Isaac Tabiri Henneh, Phyllis Owusuagyei, James Prah, Arnold Donkor Forkuo
    Abstract:

    Increasing resistance to current anti-malarial therapies requires a renewed effort in searching for alternative therapies to combat this challenge, and combination therapy is the preferred approach to address this. The present study confirms the anti-plasmodial effects of two compounds, Cryptolepine and xylopic acid and the relationship that exists in their combined administration determined. Anti-plasmodial effect of Cryptolepine (CYP) (3, 10, 30 mg kg−1) and xylopic acid (XA) (3, 10, 30 mg kg−1) was evaluated in Plasmodium berghei-infected male mice after a 6-day drug treatment. The respective doses which produced 50% chemosuppression (ED50) was determined by iterative fitting of the log-dose responses of both drugs. CYP and XA were then co-administered in a fixed dose combination of their ED50s (1:1) as well as different fractions of these combinations (1/2, 1/4, 1/8, 1/16 and 1/32) to find the experimental ED50 (Zexp). The nature of interaction between Cryptolepine and xylopic acid was determined by constructing an isobologram to compare the Zexp with the theoretical ED50 (Zadd). Additionally, the effect of Cryptolepine/xylopic acid co-administration on vital organs associated with malarial parasiticidal action was assessed. The Zadd and Zexp were determined to be 12.75 ± 0.33 and 2.60 ± 0.41, respectively, with an interaction index of 0.2041. The Zexp was significantly (P < 0.001) below the additive isobole indicating that co-administration of Cryptolepine and xylopic acid yielded a synergistic anti-plasmodial effect. This observed synergistic antiplasmodial effect did not have any significant deleterious effect on the kidney, liver and spleen. However, the testis were affected at high doses. The co-administration of Cryptolepine and xylopic acid produces synergistic anti-malarial effect with minimal toxicity.

  • in vitro anti malarial interaction and gametocytocidal activity of Cryptolepine
    Malaria Journal, 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Kwesi Boadu Mensah, Kofi Annan, Ben Gyan, Anjo Theron, Dalu Mancama, Colin W. Wright
    Abstract:

    Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, Cryptolepine. This study also investigates the anti-malarial interaction of Cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues. The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and Cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of Cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7. Cryptolepis sanguinolenta (IC50 = 49.65 nM) and its major alkaloid, Cryptolepine (IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, Cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine. The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and Cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for Cryptolepine in the development of novel fixed dose combinations.

  • identification of Cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of Cryptolepine in sprague dawley rats
    BMC Clinical Pharmacology, 2017
    Co-Authors: Arnold Donkor Forkuo, Charles Ansah, Colin W. Wright, David Pearson, Werner Gertsch, Amanda L Cirello, Adam Amaral, Jaimie Spear, Caroline Rynn
    Abstract:

    This study aims at characterizing the in vitro metabolism of Cryptolepine using human and rat hepatocytes, identifying metabolites in rat plasma and urine after a single Cryptolepine dose, and evaluating the single-dose oral and intravenous pharmacokinetics of Cryptolepine in male Sprague Dawley (SD) rats. The in vitro metabolic profiles of Cryptolepine were determined by LC-MS/MS following incubation with rat and human hepatocytes. The in vivo metabolic profile of Cryptolepine was determined in plasma and urine samples from Sprague Dawley rats following single-dose oral administration of Cryptolepine. Pharmacokinetic parameters of Cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose intravenous and oral administration. Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine and plasma of rats following oral administration of Cryptolepine. Unchanged Cryptolepine detected in urine was negligible. The Pharmacokinetic profile of Cryptolepine showed a very high plasma clearance and volume of distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma exposure and oral bioavailability were low. Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive distribution with a moderate half-life.

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  • In vitro anti-malarial interaction and gametocytocidal activity of Cryptolepine
    'Springer Science and Business Media LLC', 2017
    Co-Authors: Forkuo A.d., Ansah C., Mensah K.b., Annan K., Gyan B., Theron A., Mancama D., Wright, Colin W.
    Abstract:

    YesBackground: Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, Cryptolepine. This study also investigates the anti-malarial interaction of Cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues. Methods: The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and Cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of Cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7. Results: Cryptolepis sanguinolenta ( IC50 = 49.65 nM) and its major alkaloid, Cryptolepine ( IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, Cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine. Conclusions: The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and Cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for Cryptolepine in the development of novel fixed dose combinations

  • Identification of Cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of Cryptolepine in Sprague Dawley rats
    'Springer Science and Business Media LLC', 2017
    Co-Authors: Forkuo A.d., Ansah C., Wright, Colin W., Pearson D., Gertsch W., Cirello A., Amaral A., Spear J., Rynn C.
    Abstract:

    YesBackground: This study aims at characterizing the in vitro metabolism of Cryptolepine using human and rat hepatocytes, identifying metabolites in rat plasma and urine after a single Cryptolepine dose, and evaluating the single-dose oral and intravenous pharmacokinetics of Cryptolepine in male Sprague Dawley (SD) rats. Methods: The in vitro metabolic profiles of Cryptolepine were determined by LC-MS/MS following incubation with rat and human hepatocytes. The in vivo metabolic profile of Cryptolepine was determined in plasma and urine samples from Sprague Dawley rats following single-dose oral administration of Cryptolepine. Pharmacokinetic parameters of Cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose intravenous and oral administration. Results: Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine and plasma of rats following oral administration of Cryptolepine. Unchanged Cryptolepine detected in urine was negligible. The Pharmacokinetic profile of Cryptolepine showed a very high plasma clearance and volume of distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma exposure and oral bioavailability were low. Conclusions: Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive distribution with a moderate half-life.Funded by Novartis Pharma under the Next Generation Scientist Program

  • Cryptolepine induced apoptosis in TNFalpha-stimulated A549 lung carcinoma cells through NF-kappaB signalling pathway
    British Pharmacological Society, 2014
    Co-Authors: Olajide, Olumayokun A, Wright, Colin W.
    Abstract:

    Cryptolepine, the major alkaloid of the west African shrub Cryptolepis sanguinolenta, has been shown to induce cell cycle arrest and apoptosis in A549 cells (Zhu and Godderham, 2006). We have also reported the inhibitory effects of this compound on NF-κB in various cell types (Olajide et al., 2007; 2013a; 2013b). In this study, we have investigated whether the apoptosis-inducing action of the compound is mediated through NF-κB signalling. In order to evaluate the effect on cell proliferation, cultured A549 cells were treated with Cryptolepine (5-20 μμM) for 24 h, and number of viable cells determined using the MTT assay. Cultured cells pre-treated with Cryptolepine (5-20 μM) 30 min prior to stimulation with TNFα (1 nM) were evaluated for levels of caspase 3 using the Caspase-Glo® 3/7 Assay kit (Promega). The effects of Cryptolepine on TNFα-induced IκB phosphorylation, NF-κBp65 subunit nuclear translocation, and protein expressions of NF-κB-regulated gene products of apoptosis (cyclin D1, survivin, XIAP, cIAP1, and Bcl-2 were investigated by treating cultured A549 cells with Cryptolepine (5-20 μM) 30 min before stimulation with TNFα (1 nM), followed by In Cell western analysis. Results showed that Cryptolepine produced dose-dependent and significant (p

  • The antimalarial and cytotoxic drug Cryptolepine intercalates into DNA at cytosine-cytosine sites
    'Springer Science and Business Media LLC', 2014
    Co-Authors: Lisgarten, John N., Wright, Colin W., Portugal José, Coll Miquel, Aymamí Joan
    Abstract:

    Cryptolepine, a naturally occurring indoloquinoline alkaloid used as an antimalarial drug in Central and Western Africa, has been found to bind to DNA in a formerly unknown intercalation mode. Evidence from competition dialysis assays demonstrates that Cryptolepine is able to bind CG-rich sequences containing nonalternating CC sites. Here we show that Cryptolepine interacts with the CC sites of the DNA fragment d(CCTAGG)2 in a base-stacking intercalation mode. This is the first DNA intercalator complex, from ∼90 solved by X-ray crystallography, to bind a nonalternating (pyrimidine-pyrimidine) DNA sequence. The asymmetry of the drug induces a perfect stacking with the asymmetric site, allowing for the stability of the complex in the absence of hydrogen bonding interactions. The crystal structure of this antimalarial drug-DNA complex provides evidence for the first nonalternating intercalation and, as such, provides a basis for the design of new anticancer or antimalarial drugs.Peer Reviewe

  • Effects of the antimalarial compound Cryptolepine and its analogues in human lymphocytes and sperm in the Comet assay
    'Elsevier BV', 2011
    Co-Authors: Gopalan, Rajendran C., Wright, Colin W., Emerce E., Karahalil B., Karakaya A.e., Anderson Diana
    Abstract:

    noMalaria is a mosquito-borne infectious disease caused by the genus Plasmodium. It causes one million deaths per year in African children under the age of 5 years. There is an increasing development of resistance of malarial parasites to chloroquine and other currently used anti-malarial drugs. Some plant products such as the indoloquinoline alkaloid Cryptolepine have been shown to have potent activity against P. falciparum in vitro. On account of its toxicity, Cryptolepine is not suitable for use as an antimalarial drug but a number of analogues of Cryptolepine have been synthesised in an attempt to find compounds that have reduced cytotoxicity and these have been investigated in the present study in human sperm and lymphocytes using the Comet assay. The results suggest that Cryptolepine and the analogues cause DNA damage in lymphocytes, but appear to have no effect on human sperm at the assessed doses. In the context of antimalarial drug development, the data suggest that all Cryptolepine compounds and in particular 2,7-dibromoCryptolepine cause DNA damage and therefore may not be suitable for pre clinical development as antimalarial agents