The benzimidazole anthelmintics — chemistry and biological activity

Sharma, Satyavan; Abuzar, S.

doi:10.1007/978-3-0348-7115-0_3

Cited by 21 publications

(20 citation statements)

References 180 publications

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“…This property allows for interaction with a variety of biomolecules, resulting in the diverse range of ascribed mechanisms of action, including reduction of fumarate, glucose uptake, and microtubule inhibition (30,31). Consistent with this notion, numerous biological functions have been described for this class of compounds, including antihelminthic, antifungal, antimicrobial, antiviral, and antineoplastic activity (32)(33)(34). Given the variety of these activities, previous studies have suggested that inhibition of cellular proliferation by mebendazole may involve effects in addition to its microtubule disruption properties.…”

Section: Discussionmentioning

confidence: 83%

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Doudican¹,

Rodriguez²,

Osman

et al. 2008

Molecular Cancer Research

128

114

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Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 Mmol/L using two chemoresistant melanoma cell lines ) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC 50 of 0.32 Mmol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent. (Mol Cancer Res 2008;6(8):1308 -15)

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Section: Discussionmentioning

confidence: 83%

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Doudican¹,

Rodriguez²,

Osman

et al. 2008

Molecular Cancer Research

128

114

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“…Benzimidazole class of com pound possessing high order of activity against in testinal and to the extent against tissue dwelling helminths (Sharma and Abuzar, 1983) have sev eral set backs (Townsend and Wise, 1990) and thus there is need for search for new structural proto types having macrofilaricidal property.…”

Section: Introductionmentioning

confidence: 99%

Structure-Antifilarial Activity Relationship of 5/6/7/8-Mono-or Disubstituted 1H/1-Phenyl-9H-pyrido[3,4-b]indoles -A New Class of Potential Filaricides

Agarwal¹,

Agarwal²,

Singh

et al. 1994

Zeitschrift Für Naturforschung C

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IntroductionThe successful treatm ent of filariasis, a disease of many tropical and subtropical areas, is jeop ardized, due to lack of suitable chemotherapeutic agents capable of eliminating both microfilariae and adult worms with least toxicity to the host (Agarwal et al., 1993). Benzimidazole class of com pound possessing high order of activity against in testinal and to the extent against tissue dwelling helminths (Sharma and Abuzar, 1983) have sev eral set backs (Townsend and Wise, 1990) and thus there is need for search for new structural proto types having macrofilaricidal property.In our earlier studies, substituted 9H-pyrido-[3,4-b]indoles (ß-carbolines) (Agarwal et al., 1989, 1990a, 1990b; Kumar et al., 1990) exhibited prom ising anthelmintic activity against intestinal hel minths. Therefore, it is proposed to explore this class of compounds for filarial chemotherapy. Accordingly, 5/6/7/8-mono-or disubstituted 1 H/ l-phenyl-9H-pyrido [3,4-b]indoles (I) were synthe sized and evaluated for antifilarial activity against L itom osoides carinii and Acanthocheilonem a vitae in rodents. Materials and Methods SynthesisThe various 5/6/7/8-mono-or disubstituted 1 H/ l-phenyl-9H-pyrido[3,4-b]indoles (I , Table I) Parasites and hostsAll the compounds were evaluated against L. carinii in cotton rats (Sigm odon hispidus) and A. viteae in M astom ys natalensis. As the com pounds were insoluble in water fine suspensions of each one of them was m ade in presence of 1 % Tween 80 (Katiyar et al., 1984). Two to three ani mals were used for each dose level study and at least two replicates were used for confirmation of activity. Evaluation o f antifilarial activity Litom osoides cariniiThe infection was transm itted to 6 weeks old male cotton rats (Sigm odon hispidus) through the vector Liponyssus bacoti by the literature method (Hawking and Sewell, 1948). Animals showing 250 or more microfilariae per 5 mm3 of blood were chosen for screening. Blood samples of exper imental and control animals were examined for microfilariae before starting the treatm ent and thereafter at weekly interval till day 42. All the compounds were given 30 mg/kg intraperitoneally for 5 consecutive days. On day 42, all the treated and control animals were sacrified and the con dition of adult male and female worms observed. The micro-and macrofilaricidal action were as sessed by literature m ethod (Lämmler et al., 1971;Misra et al., 1981).

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“…Based on the broad-spectrum of anthelmintic activity asso ciated with various benzimidazole drugs [22] a to tal of thirteen benzimidazoles (1 -13) carrying dif ferent pharmacophores at their 2 and 5 positions were valuated against L. carinii. O f these, com pounds 1 -3 , 6 -8 and 9 showed marked effect on the reproductive system o f the females.…”

Section: Resultsmentioning

confidence: 99%

Chemotherapy of Filariasis -On the Search of New Agents Effective on the Reproductive System of Female Adult Worms

Singh

Seth

Fatma

et al. 1990

Zeitschrift Für Naturforschung C

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The benzimidazole anthelmintics — chemistry and biological activity

Cited by 21 publications

References 180 publications

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Structure-Antifilarial Activity Relationship of 5/6/7/8-Mono-or Disubstituted 1H/1-Phenyl-9H-pyrido[3,4-b]indoles -A New Class of Potential Filaricides

Chemotherapy of Filariasis -On the Search of New Agents Effective on the Reproductive System of Female Adult Worms

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