Preparation of transition-state analogues of sterol 24-methyl transferase as potential anti-parasitics

Lorente, Silvia Orenes; Jimenez, Carmen Jimenez; Gros, Ludovic; Yardley, Vanessa; Luca-Fradley, Kate de; Croft, Simon L.; Urbina, Julio A.; Pérez, Luis; González-Pacanowska, Dolores; Gilbert, Ian H.

doi:10.1016/j.bmc.2005.06.012

Cited by 38 publications

(34 citation statements)

References 36 publications

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“…Encouraged by those findings, we decided to extend the range of azasterols; some of these compounds were active against bloodstream form Trypanosoma brucei subsp. rhodesiense, the causative organism of human African trypanosomiasis (7,8).…”

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confidence: 99%

New Azasterols against Trypanosoma brucei : Role of 24-Sterol Methyltransferase in Inhibitor Action

Gros

Castillo-Acosta

Jimenez

et al. 2006

Antimicrob Agents Chemother

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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 activity. None of the inhibitors tested appeared to be active against the enzyme. Sterol composition analysis showed that only cholestane type sterols are present in membranes of bloodstream forms while ergosterol is a major component of procyclic sterol extracts. Interestingly, Northern blot analysis showed the presence of 24-SMT mRNA in both the procyclic and the bloodstream forms of the parasite, although levels of mRNA were threefold lower in the latter. Likewise, Western blot analysis and activity determinations evidenced the existence of active enzyme in both forms of the parasite. We conclude that the designed compounds act at sites other than 24-SMT in Trypanosoma brucei.

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confidence: 99%

New Azasterols against Trypanosoma brucei : Role of 24-Sterol Methyltransferase in Inhibitor Action

Gros

Castillo-Acosta

Jimenez

et al. 2006

Antimicrob Agents Chemother

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“…These observations led to the discovery that tipifarnib also inhibits trypanosomal cytochrome P450 sterol 14-demethylase [91]. Sterols related to 35 were found to be excellent growth inhibitors in L. donovanii, L. major, and T. cruzi with relatively low toxicity to host cells [92,93]. It was later determined that compound 35 and its homologs are potent transition state analog inhibitors of 24-sterol methyltransferase from L. major [93].…”

Section: Inhibitors Of Parasitic Lipid Metabolismmentioning

confidence: 95%

“…Sterols related to 35 were found to be excellent growth inhibitors in L. donovanii, L. major, and T. cruzi with relatively low toxicity to host cells [92,93]. It was later determined that compound 35 and its homologs are potent transition state analog inhibitors of 24-sterol methyltransferase from L. major [93]. Some analogs in the series were also effective against T. b. rhodesiense, although this effect was mediated at a site other than trypanosomal 24-sterol methyltransferase.…”

Section: Inhibitors Of Parasitic Lipid Metabolismmentioning

confidence: 99%

Antiprotozoal/Antiparasitic Agents

Woster

2010

Burger's Medicinal Chemistry and Drug Discovery

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Collectively, diseases caused by parasitic protozoa, including human African trypanosomiasis ( HAT ), Chagas' disease and leishmaniasis, threaten more than 550 million people worldwide and cause nearly 150,000 deaths annually. The causative organisms for these diseases are unicellular trypanosomatid parasites of the genera Trypanosoma brucei , Trypanosoma cruzi , and Leishmania sp., respectively. Drug therapies available for these diseases have not changed significantly in the past 50 years, and currently used agents are far less than satisfactory due to extreme toxicity, and because resistant parasitic strains are becoming more prevalent. These diseases are confined to impoverished or rural areas of Mexico, Central America, South America, sub‐Saharan Africa, the Middle East, Indonesia, and India. As such, drug discovery efforts against trypanosomatid diseases are limited because patients in underdeveloped areas cannot afford therapy, and because the infected population is too small to justify the required research expenditures. In addition, antiparasitic research in Third World nations is often hampered by economic issues and political turmoil, virtually assuring that the world's most impoverished people will continue to bear the major burden of parasitic disease. Clearly, there is a need for new anti‐infective agents that are potent, nontoxic and inexpensive to manufacture. In this chapter, the etiology of these diseases and their current treatment are described. The chapter also deals with medicinal chemistry aspects of efforts to identify new drug targets for parasitic diseases, and to produce novel inhibitors of trypanosomatid growth for use as antiparasitic agents.

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“…Some azasterols able to inhibit 24-methyltransferase showed antileishmanial activity. However, other compounds of the same family that did not affect the enzyme showed nonetheless antileishmanial activity by a mechanism that still needs to be elucidated [178,179]. Sterols synthesis may also be affected by plant extracts: sterols isolated from the roots of the plant Pentalion andrieuxii showed marked antileishmanial activity [180], as well as the steroidal glycoalkaloid α-tomatine, derived from Lycopersicon aesculentum [181].…”

Section: Target-based Development Of New Drugsmentioning

confidence: 99%

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

Zucca¹,

Scutera²,

Savoia³

2013

Current Medicinal Chemistry

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Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites. However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance. In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return. The establishment of adequately funded public-private partnerships is currently reversing the trend. This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development. The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews.

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Preparation of transition-state analogues of sterol 24-methyl transferase as potential anti-parasitics

Cited by 38 publications

References 36 publications

New Azasterols against Trypanosoma brucei : Role of 24-Sterol Methyltransferase in Inhibitor Action

New Azasterols against Trypanosoma brucei : Role of 24-Sterol Methyltransferase in Inhibitor Action

Antiprotozoal/Antiparasitic Agents

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

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