2006
DOI: 10.1128/aac.01508-05
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Abstract: A series of azasterol derivatives, designed as potential inhibitors of the ⌬ 24 -sterol methyltransferase enzyme (24-SMT), were synthesized and evaluated for their activities against parasitic protozoa. Values in the nanomolar range were obtained for 50% effective dose against the Trypanosoma brucei subsp. rhodesiense bloodstream form cultured in vitro. In order to investigate the mode of action, Trypanosoma brucei subsp. brucei 24-SMT was cloned and overexpressed and compounds were assayed for inhibitory acti… Show more

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Cited by 37 publications
(49 citation statements)
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“…The bloodstream form of T. brucei is thought to scavenge sterols from the human host, although procyclic T. brucei has an active ergosterol biosynthetic pathway that includes the enzyme SQS. Interestingly, we have recently shown that although the bloodstream form of T. brucei scavenges sterols from the human host and does not synthesize ergosterol, it does expresses sterol 24-methyltransferase, another enzyme involved in ergosterol biosynthesis (14). P. falciparum, in contrast, lacks the enzymes involved in sterol biosynthesis beyond farnesyl diphosphate synthase, as inferred from genomic data.…”
Section: Discussionmentioning
confidence: 99%
“…The bloodstream form of T. brucei is thought to scavenge sterols from the human host, although procyclic T. brucei has an active ergosterol biosynthetic pathway that includes the enzyme SQS. Interestingly, we have recently shown that although the bloodstream form of T. brucei scavenges sterols from the human host and does not synthesize ergosterol, it does expresses sterol 24-methyltransferase, another enzyme involved in ergosterol biosynthesis (14). P. falciparum, in contrast, lacks the enzymes involved in sterol biosynthesis beyond farnesyl diphosphate synthase, as inferred from genomic data.…”
Section: Discussionmentioning
confidence: 99%
“…[18][19][20] We have also prepared some squalamine analogues which have some anti-leishmanial activity. 21 These azasterols that we have reported [10][11][12][13][14] have interesting in vitro activity against T. brucei rhodesiense and Leishmania donovani. From the evaluation of these compounds it was possible to construct a preliminary pharmacophore for the activity against T. brucei rhodesiense.…”
Section: Introductionmentioning
confidence: 97%
“…1). [10][11][12][13][14] We noticed that some of these compounds were active against bloodstream form (bsf) T. brucei; however bsf T. brucei is reported to scavange cholesterol from the host, rather than biosynthesise ergosterol, 15,16 suggesting alternate modes of action for these compounds. We also discovered that some compounds had multiple modes of action against Leishmania spp.…”
Section: Introductionmentioning
confidence: 99%
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“…Human farnesyl diphosphate synthase is the target of bisphosphonates (e.g., tiludronate), used against osteoporosis ( 10 ). Squalene epoxidase and sterol 24-methyltransferase are antifungal targets, inhibited by allylamines (e.g., terbinafi ne) and azasterols, respectively (11)(12)(13)(14). A particularly promising target is sterol 14-demethylase (CYP51).…”
Section: Sequencesmentioning
confidence: 99%