Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-d]pyrimidines

Jorda, Radek; Sacerdoti‐Sierra, Nina; Voller, Jiří; Havlı́cěk, Libor; Kráčalíková, Kateřina; Nowicki, Matthew W.; Nasereddin, Abedelmajeed; Kryštof, Vladimı́r; Strnad, Miroslav; Walkinshaw, Malcolm D.; Jaffe, Charles L.

doi:10.1016/j.bmcl.2011.05.076

Cited by 41 publications

(22 citation statements)

References 29 publications

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“…Among the various families of protein kinases so far identified, the most studied are the cyclin-dependent and the mitogen-activated protein kinases. Members of the former family have been characterized as potential targets for cancer therapy, and the screening of a library of inhibitors of human cyclin-dependent kinases against axenic amastigotes of L. donovani showed that a series of disubstituted pyrazol [4-3d]pyrimidines is active in a 1.5-12.4 µM range [175]. In addition, several small chemical inhibitors of cyclin-dependent kinases are undergoing clinical trials to assess their effectiveness in cancer treatment.…”

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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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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“…However, none of the compounds found to be potent against the parasite showed selectivity for CRK3 over mammalian CDK1/cyclin B. Recently, 18 isomeric pairs of 6,9-disubstituted purines and corresponding 3,7-disubstituted pyrazolo[4,3-d]pyrimidines (Figure 4.1), which previously were shown to inhibit human CDK1, were tested on recombinant Leishmania CRK3:CYC6 [42]. The pyrazolo [4,3-d]pyrimidines were found to be more potent inhibitors of the CDK complex than the purines, with several of the identified compounds having IC 50 values of $2-20 mM.…”

Section: Crk3mentioning

confidence: 99%

Trypanosomatid Cell Division Kinases

Benz

Thomas

Hammarton

2013

Protein Phosphorylation in Parasites

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Advances have been made recently in understanding the order of events in the cell division cycles of Leishmania spp. and Trypanosoma cruzi, adding to previous knowledge of events in Trypanosoma brucei, and highlighting similarities and differences between these trypanosomatids. However, the present understanding of how the cell cycle is regulated by kinases still largely derives from analyses in T. brucei, since convenient genetic tools for analyzing the function of essential regulators -for example, inducible expression systems and/or RNA interferenceare still lacking in Leishmania and T. cruzi. While current understanding of the function of some kinases (e.g., some cyclin-dependent kinases, the NDR kinases, aurora, tousled-like and polo-like kinases) is now very good, many more remain to be characterized, as do details of the signal transduction pathways in which they operate. A number of protein kinases have, in recent years, been genetically -and in some cases also chemically -validated as potential novel drug targets for human African trypanosomiasis or leishmaniasis, although only a few, including CRK3: CYC6, CRK3:CYCA, the NDR kinases, PK50 and PK53 and polo-like kinase, have been subjected to high-throughput screening to identify small-molecule inhibitors. However, problems with these screens include a failure to identify potent inhibitors against the parasite enzyme in vitro, a lack of selectivity for the parasite enzyme over the equivalent human enzyme, or poor efficacy against the parasite. Thus, further chemical investigations will be required to generate new compounds with more ideal properties.

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“…CC 50 , cytotoxic concentration of a drug required to inhibit 50% of any subject in vitro [3,22]. EC 50 , 50% effective plasma concentration at which the effectiveness is 50% of the maximum for this drug in vivo [3,7,9,22]. ID, inhibiting dose; IC, inhibiting concentration, IC 50 , [5,6,9,10,41]; ID 80 , [3]; ID 95 , [28].…”

mentioning

confidence: 99%

Biological Activity of Adamantane-Containing Mono- and Polycyclic Pyrimidine Derivatives* (A Review)

Shokova

Ковалев

2016

Pharm Chem J

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Biological test results for a series of adamantane-containing pyrimidines, purines, and their derivatives that were synthesized and studied in 1999 -2001 are reviewed. Pyrimidine, purine, and similar scaffolds are exceedingly common key building blocks in the design of drugs with the broadest spectra of action comprising antibacterial, antiviral, antitumor, neurotropic, antifungal, immunotropic, and other types of drugs. An adamantane moiety in the molecules often has a substantial effect on the biological properties. Practically all studies included in the first part of the present review [1] explain their goals using just such factors. Therefore, almost every study consisted of two parts, i.e., chemical and biological.The previous studies focused on synthetic pyrimidine derivatives such as monocyclic pyrimidines (pyrimidinone, uracil, cytosine, uridines, etc.), condensed di-and polycyclic compounds (pyrazolopyrimidine, triazolopurine, xanthene, etc.), and adenosines with various substitution patterns and types of substituents. An adamantane moiety could be either bonded directly to the heterocycle or on its periphery. This part of the review focuses on biological tests of the synthesized compounds**. The subsections present research results according to individual type of biological activity. In addition, a subsection called Biological Screening was included. It includes results for instances where the activity of certain rather large groups (types) of compounds was studied for several rather than a single indication. This was most often related to characteristic antimicrobial, fungicidal, and antimalarial activity and the cytotoxicity of the drugs. In most instances, we considered it counterproductive to lump these results into piles in various sections. * Part 1 of the present review [1] contains information regarding the synthesis of adamantane-containing pyrimidine derivatives. ** The following terms [abbreviation and its explanation (if it exists) given in the corresponding publication] are used to present the biological test results:MIC, minimum inhibiting concentration [2, 3, 6]. MIC 50 , minimum inhibiting concentration suppressing development of virus-induced cytopathic activity by 50% [23,51]. MCC 50 , minimum cytotoxic concentration causing 50% inhibition of cell growth (VERO cells) [23,51]. CD 50 , cytotoxic dose causing 50% inhibition of cell growth [28]. CC 50 , cytotoxic concentration of a drug required to inhibit 50% of any subject in vitro [3,22]. EC 50 , 50% effective plasma concentration at which the effectiveness is 50% of the maximum for this drug in vivo [3,7,9,22]. ID, inhibiting dose; IC, inhibiting concentration, IC 50 , [5,6,9,10,41]; ID 80 , [3]; ID 95 , [28]. SI, selectivity index; SI = MCC 50 /MIC 50 [23, 51]; SI = CC 50 /EC 50 [3, 22]; SI = CD 50 /ID 50 [28]. pEC 50 , negative logarithm of EC 50 [46]. K i , equilibrium dissociation constant [42, 44, 45].

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Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-d]pyrimidines

Cited by 41 publications

References 29 publications

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

Trypanosomatid Cell Division Kinases

Biological Activity of Adamantane-Containing Mono- and Polycyclic Pyrimidine Derivatives* (A Review)

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