Chemotherapeutic agents XI: synthesis of pyrimidines and azolopyrimidines as leishmanicides

Ram, Vishnu Ji; Singha, U. K.; Guru, P. Y.

doi:10.1016/0223-5234(90)90148-v

Cited by 65 publications

(40 citation statements)

References 7 publications

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“…Some efforts have been devoted to searching for new antileishmanial drugs during the past 2 decades (2,6,15,21,22,25,30,33,38). One of the strategies for development of new antileishmanial drugs is to identify some unique enzymes, which exist only in the parasite and play important role in energy metabolism, as targets, and then to find or design inhibitors of these enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…This resistance occurred in 5 to 70% of patients in some areas of endemicity (28, 36). There is, therefore, a great and urgent need for the development of new, effective, and safe drugs for the treatment of leishmaniasis.A number of investigations to explore potential antileishmanial drugs have been carried out during the last 2 decades (2,6,15,21,22,25,30,33,38). We have previously reported that chalcones have potent antileishmanial and antimalarial activities and might be developed into a new class of antileishmanial drugs (7-10, 39).…”

mentioning

confidence: 99%

“…A number of investigations to explore potential antileishmanial drugs have been carried out during the last 2 decades (2,6,15,21,22,25,30,33,38). We have previously reported that chalcones have potent antileishmanial and antimalarial activities and might be developed into a new class of antileishmanial drugs (7)(8)(9)(10)39).…”

mentioning

confidence: 99%

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Inhibition of Fumarate Reductase in Leishmania major and L. donovani by Chalcones

Chen

Zhai

Christensen

et al. 2001

Antimicrob Agents Chemother

201

130

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Our previous studies have shown that chalcones exhibit potent antileishmanial and antimalarial activities in vitro and in vivo. Preliminary studies showed that these compounds destroyed the ultrastructure of Leishmania parasite mitochondria and inhibited the respiration and the activity of mitochondrial dehydrogenases of Leishmania parasites. The present study was designed to further investigate the mechanism of action of chalcones, focusing on the parasite respiratory chain. The data show that licochalcone A inhibited the activity of fumarate reductase (FRD) in the permeabilized Leishmania major promastigote and in the parasite mitochondria, and it also inhibited solubilized FRD and a purified FRD from L. donovani. Two other chalcones, 2,4-dimethoxy-4-allyloxychalcone (24m4ac) and 2,4-dimethoxy-4-butoxychalcone (24mbc), also exhibited inhibitory effects on the activity of solubilized FRD in L. major promastigotes. Although licochalcone A inhibited the activities of succinate dehydrogenase (SDH), NADH dehydrogenase (NDH), and succinate-and NADHcytochrome c reductases in the parasite mitochondria, the 50% inhibitory concentrations (IC 50 ) of licochalcone A for these enzymes were at least 20 times higher than that for FRD. The IC 50 of licochalcone A for SDH and NDH in human peripheral blood mononuclear cells were at least 70 times higher than that for FRD. These findings indicate that FRD, one of the enzymes of the parasite respiratory chain, might be the specific target for the chalcones tested. Since FRD exists in the Leishmania parasite and does not exist in mammalian cells, it could be an excellent target for antiprotozoal drugs.Leishmaniasis is a major and increasing public health problem, particularly in Africa, Asia, and Latin America (23, 37). Some 350 million people are at risk of infection with Leishmania spp., and more than 12 million people are infected with different species of the parasite. Each year, there are 1.5 million new cases, and 500,000 of these are visceral leishmaniasis, which is nearly always fatal if left untreated (23). Treatment of leishmaniasis is unsatisfactory in that the existing drugs require repeated parenteral administration, and none of them are effective in all cases or are totally free of side effects (1, 26, 37). Furthermore, large-scale clinical resistance to antimonials, the first-line antileishmanial drugs, has been reported recently. This resistance occurred in 5 to 70% of patients in some areas of endemicity (28, 36). There is, therefore, a great and urgent need for the development of new, effective, and safe drugs for the treatment of leishmaniasis.A number of investigations to explore potential antileishmanial drugs have been carried out during the last 2 decades (2,6,15,21,22,25,30,33,38). We have previously reported that chalcones have potent antileishmanial and antimalarial activities and might be developed into a new class of antileishmanial drugs (7-10, 39). Attempting to elucidate the antileishmanial mechanism of action of the chalcones, we have previously fou...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of Fumarate Reductase in Leishmania major and L. donovani by Chalcones

Chen

Zhai

Christensen

et al. 2001

Antimicrob Agents Chemother

201

130

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“…21 In addition, triazolo [4,3-a]pyrimidine derivatives were reported to be useful as antihypertensive, 22 anxiolytic, 23 and cardiovascular 24,25 agents.…”

Section: −6mentioning

confidence: 99%

Synthesis and biological evaluation of novel fused triazolo[4,3-$a$] pyrimidinones

Abbas¹,

Gomha²,

Elneairy³

et al. 2015

Turk J Chem

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The reaction of thione 3 or its 2-methylthio derivative 4 with hydrazonoyl halides 5a-l, in the presence of triethylamine, yielded the corresponding triazolo[4,3-a ]pyrimidin-5(1 H) -ones 8a-l. The structure of compounds 8a-l was further confirmed by the reaction of 3 with the appropriate active chloromethylenes 11a-c followed by coupling of the products with benzenediazonium chloride to afford the azo-coupling products 6b, f, and j, which were converted in situ to 8b, f, and j. 2-Hydrazinyl-pyrido[3',2':4,5]thieno[3,2-d ]pyrimidin-4(3 H) -one ( 13) was prepared and condensed with different aldehydes 14a-f to give the corresponding hydrazone derivatives 15a-f. Oxidative cyclization of the hydrazones 15a-f give the corresponding triazolo[4,3-a ] pyrimidin-5(1 H) -one derivatives 16a-f.The antimicrobial activity of the products was evaluated and the results revealed that compounds 8f and 15f showed strong activity against gram-positive bacteria while compound 15d showed the highest activity against gramnegative bacteria. Moreover, compounds 15b, 8d, 8e, 8c, 8l, and 8j exhibited significant antifungal activity. In addition, the antitumoral activity of the synthesized products against different cancer cell lines was determined and the results revealed that compound 12c was the most active against MCF-7, HepG-2, HCT-116, and HeLa with IC 50 values of 0.51, 0.72, 0.95, and 0.95, respectively, as compared with doxorubicin as positive control.

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“…5 Pyrimidines are the basic nucleus in nucleic acids and have been associated with a number of biological activities. 6 Substituted aminopyrimidine nuclei are common in marketed drugs such as anti-atherosclerotic aronixil, anti-histaminic thonzylamine, anti-anxielytic buspirone, anti-psoriatic enazadrem, and other medicinally relevant compounds.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Spectral Characterization of Novel 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides

Kanagarajan¹,

Thanusu²,

Gopalakrishnan³

2010

Journal of the Korean Chemical Society

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Chemotherapeutic agents XI: synthesis of pyrimidines and azolopyrimidines as leishmanicides

Cited by 65 publications

References 7 publications

Inhibition of Fumarate Reductase in Leishmania major and L. donovani by Chalcones

Inhibition of Fumarate Reductase in Leishmania major and L. donovani by Chalcones

Synthesis and biological evaluation of novel fused triazolo[4,3-$a$] pyrimidinones

Design, Synthesis and Spectral Characterization of Novel 2-morpholino-N-(4,6-diarylpyrimidin-2-yl)acetamides

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