Synthesis and Biological Activity of Sterol 14α-Demethylase and Sterol C24-Methyltransferase Inhibitors

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Term Occurence Count Dictionary
Ketoconazole 5 infectiousdiseasesdrugs
candidiasis 3 infectiousdiseases
cutaneous leishmaniasis 1 infectiousdiseases
oxiconazole 1 infectiousdiseasesdrugs
Itraconazole 9 infectiousdiseasesdrugs
Chagas disease 10 infectiousdiseases
eflornithine 1 infectiousdiseasesdrugs
fluconazole 15 infectiousdiseasesdrugs
sleeping sickness 2 infectiousdiseases
trypanosomiasis 4 infectiousdiseases
AIDS 2 infectiousdiseases

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Select Drug Character Offset Drug Term Instance
Itraconazole 14171 Pharmaceutica in the early 1990s and was active against both Candida spp. and Aspergillus spp. [[17]]. Itraconazole from Janssen Pharmaceutica, Beerse, Belgium was approved for use in 1992, while posaconazole (Noxafil®)
Itraconazole 20100 reacted with the sodium salt of 1 acetyl-4-(4-hydroxyphenyl)piperazine to produce ketoconazole [[31]]. Itraconazole has MIC90 values ranging from 0.03 to 64 μg/mL against various Candida spp. and a MIC90 value of 2.7
Itraconazole 20256 μg/mL against various Candida spp. and a MIC90 value of 2.7 μg/mL against Malassezia furfur [[12]]. Itraconazole was noted to have potent in vitro activity against C. neoformans [[67]]. Itraconazole was observed to
Itraconazole 20342 furfur [[12]]. Itraconazole was noted to have potent in vitro activity against C. neoformans [[67]]. Itraconazole was observed to successfully achieve irreversible damage against various fungi, including C. albicans,
Itraconazole 20553 albicans, C. neoformans, T. rubrum, Paracoccidiodes brasiliensis, and Aspergillus fumigatus [[12],[68]]. Itraconazole absorption is enhanced by food intake, and oral solutions provide higher serum concentrations in comparison
Itraconazole 20704 and oral solutions provide higher serum concentrations in comparison to capsules [[12],[69],[70]]. Itraconazole is very active in vitro against Microsporum canis and other dermatophytes associated with scalp ringworm
Itraconazole 21012 was reported to be 25, which was much better than the selectively index of ketoconazole [[53],[71]]. Itraconazole was observed to have an ED50 value of 1 μM against T. brucei parasites, and when combined with 25-azalanosterol
Itraconazole 21177 T. brucei parasites, and when combined with 25-azalanosterol (AZAL), parasite death resulted [[2]]. Itraconazole exhibited in vitro activity against Leishmania mexicana mexicana amastigotes in macrophages, and 50%
Itraconazole 21429 observed at 0.15 μM, which was more potent than that observed for ketoconazole (0.21 μM) [[72]]. Itraconazole has been reported to successfully treat cutaneous leishmaniasis; however, it was not as effective against
Ketoconazole 18593 radioactivity in most organs was observed in both species upon equilibration of [4-18F]fluconazole [[38]]. Ketoconazole developed by Janssen Pharmaceutica was approved by the FDA in 1981 and was the first broad-spectrum
Ketoconazole 18839 activity; its reported MIC90 values range from 0.06 to 4 μg/mL against various Candida spp. [[12],[53]]. Ketoconazole is highly active against Trichophyton mentagrophytes at 0.1 μg/mL, while Trichophyton rubrum and C.
Ketoconazole 18998 mentagrophytes at 0.1 μg/mL, while Trichophyton rubrum and C. neoformans are inhibited at 1 μg/mL [[12]]. Ketoconazole has been shown to prolong the survival of mice infected with T. cruzi; however, curing effects were
Ketoconazole 19137 the survival of mice infected with T. cruzi; however, curing effects were not observed [[63],[64]]. Ketoconazole has a reported Kd value of 4.4 μM against cloned TbCYP51 [[65]]. Ketoconazole at a concentration of
Ketoconazole 19216 observed [[63],[64]]. Ketoconazole has a reported Kd value of 4.4 μM against cloned TbCYP51 [[65]]. Ketoconazole at a concentration of 0.1 μM in conjunction with 24(R,S)-25-epiminolanosterol (EL) at a concentration
eflornithine 37700 sample of 26-FCT [[5]]. 26-FCT has an excellent partition ration of 1.08, comparing favorably with eflornithine , which has a partition ratio of 3.3 against L-ornithine decarboxylase [[5]]. Both 26-FL and 26-FCT exhibit
fluconazole 13793 [[53],[54]]. Some of the classic azoles used as standards for fungal SDM inhibition include ketoconazole, fluconazole , itraconazole, and posaconazole, and structures of these drugs are shown in Figure 11. Fluconazole (Diflucan®)
fluconazole 15747 candidiasis model, making it 50 times more potent than ketoconazole [[57]]. The plasma half-life for fluconazole was 6.1 h, and 75% of the drug was excreted in urine with no changes to its structure [[12]]. The 2,4-difluorophenyl
fluconazole 16446 of 0.23 μM against T. cruzi SDM and an EC50 value of approximately 40 μM against T. cruzi, while fluconazole has a Kd value of 0.34 μM for T. brucei SDM [[21],[58]]. Fluconazole has an in vitro IC50 value of
fluconazole 16642 vitro IC50 value of 8 μM against T. cruzi, and a crystal structure of T. cruzi SDM cocrystallized with fluconazole has been reported [[21],[59],[60],[61]]. A 6 week oral course of fluconazole was shown to be safe and
fluconazole 16719 SDM cocrystallized with fluconazole has been reported [[21],[59],[60],[61]]. A 6 week oral course of fluconazole was shown to be safe and useful for treating leishmaniasis caused by Leishmania major [[62]].There are
fluconazole 16871 treating leishmaniasis caused by Leishmania major [[62]].There are several different ways to synthesize fluconazole . One of the popular routes is the oxirane ring opening of 1-[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole
fluconazole 17090 1-[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole with 1,2,4-triazole and potassium carbonate [[17]]. One of the more recent syntheses of fluconazole uses a semi-continuous flow method (Figure 12) [[39]]. 2,4-Difluorobromobenzene (21) was reacted with
fluconazole 17422 1,3-dichloroacetone (22) to yield 2-(2,4-difluorophenyl)-1,3-dichloro-2-propanol (23) [[39]]. The synthesis of fluconazole was completed with the nucleophilic attack of intermediate 23 with two 1,2,4-triazoles without using
fluconazole 17585 intermediate 23 with two 1,2,4-triazoles without using flow chemistry [[39]].An interesting synthesis of fluconazole is the 18F-labeled synthesis of [4-18F]fluconazole (Figure 13) [[38]]. Under Friedyl–Crafts acylation
fluconazole 17636 flow chemistry [[39]].An interesting synthesis of fluconazole is the 18F-labeled synthesis of [4-18F] fluconazole (Figure 13) [[38]]. Under Friedyl–Crafts acylation conditions, m-fluoroacetanilide (24) was reacted
fluconazole 18333 potassium [18F]-fluoride [[38]]. [4-18F]Fluconazole was synthesized to measure the pharmacokinetics of fluconazole in rats by radioactive measurements of excised tissues and in rabbits by positron emission tomography
fluconazole 18574 distribution of radioactivity in most organs was observed in both species upon equilibration of [4-18F] fluconazole [[38]].Ketoconazole developed by Janssen Pharmaceutica was approved by the FDA in 1981 and was the first
fluconazole 25936 excellent selectivity index (human/T. cruzi of >50,000) [[14]]. An advantage of VNI, unlike posaconazole or fluconazole , is that it does not induce T. cruzi gene expression, which means it is not as likely to cause drug
fluconazole 42208 4,4-dimethyl-14α-aminomethyl-cholest-8-en-3β-ol (12).Figure 11Azole inhibitors of sterol 14α-demethylase (SDM).Figure 12Synthesis of fluconazole using flow-injection methodology (adapted from [[39]]).Figure 13Synthesis of [4-18F]fluconazole.Figure
fluconazole 42304 of fluconazole using flow-injection methodology (adapted from [[39]]).Figure 13Synthesis of [4-18F] fluconazole .Figure 14Synthesis of ketoconazole.Figure 15The synthesis of itraconazole.Figure 16Synthesis of posaconazole.Figure
oxiconazole 12544 properties. 1,2,4-Triazole fungicides such as difenoconazole (Score® (Syngenta, Basel, Switzerland)), ep oxiconazole (Opal® (TRC, North York, ON, Canada)), flusilazole (Punch® (DuPunt, Wilmington, DE, USA)), and so
Select Disease Character Offset Disease Term Instance
AIDS 3193 neoformans have become the leading cause of morbidity and mortality in acquired immune deficiency syndrome ( AIDS ) patients and other immunocompromised patients, and it is reported that 5–10% of AIDS patients in
AIDS 3281 deficiency syndrome (AIDS) patients and other immunocompromised patients, and it is reported that 5–10% of AIDS patients in the United States suffer from these life-threatening infections [[12],[13]].Selective inhibition
Chagas disease 850 using SDM inhibitors to treat neglected tropical diseases such as human African trypanosomiasis (HAT), Chagas disease , and leishmaniasis. Sterol C24-methyltransferase (24-SMT) introduces the C24-methyl group of ergosterol
Chagas disease 2349 while the World Health Organization (WHO) has estimated that 16–18 million people are infected with Chagas disease [[10]], and it has been suggested that 70 million people in Africa are at risk of human African trypanosomiasis
Chagas disease 14831 11), a new-generation imidazole, has been shown to exert a curative effect for both acute and chronic Chagas disease in a murine model with 100% survival and no observable side effects [[14],[55]]. VNI is available at
Chagas disease 15143 pharmacokinetics, which makes this compound an attractive candidate for clinical trials to treat patients with Chagas disease [[55]].Fluconazole is a water-soluble, well-tolerated, and cheap first-generation antifungal drug that
Chagas disease 21787 experimentally infected animals or human patients in studies investigating it as a possible treatment for Chagas disease [[76]].The synthesis of itraconazole can be started by reacting compound 30 with sodium hydride and
Chagas disease 23369 [[78]]. Posaconazole demonstrated potent in vivo anti-parasitic activity in a murine model of acute Chagas disease , which was most likely due to its high binding affinity for TcCYP51, good pharmacokinetic properties,
Chagas disease 23868 strains and is able to induce radical parasitological cures in both chronic and acute experimental Chagas disease [[76]]. An Argentinean woman in Spain who suffered from chronic Chagas disease was successfully treated
Chagas disease 23947 and acute experimental Chagas disease [[76]]. An Argentinean woman in Spain who suffered from chronic Chagas disease was successfully treated with posaconazole, although requiring concurrent immunosuppressive therapy
Chagas disease 24506 widespread use in developing countries even if it is successful in obtaining approval for treating Chagas disease [[55],[77],[79]].One of the well-established synthetic routes for the synthesis of posaconazole starts
Chagas disease 40481 trials. Posaconazole was investigated in two phase II clinical trials as a possible agent to treat Chagas disease , and on the basis of the results provided thus far, it is unlikely that posaconazole will progress to
candidiasis 15646 50% (ED50) of the murine population with <1.0 mg/kg for 5 days when orally administered in a murine candidiasis model, making it 50 times more potent than ketoconazole [[57]]. The plasma half-life for fluconazole
candidiasis 23001 States of America (2006) as a prophylactic for invasive fungal infections in addition to azole-resistant candidiasis [[77]]. Posaconazole was observed to have a MIC value of 20 nM and an IC50 value of 14 nM against the
candidiasis 39769 ranging from <0.1 to 50 mg/mL [[106]]. Compounds 57 and 58 were then tested in vivo against a murine candidiasis antifungal model, and unfortunately both compounds were ineffective against the induced infection. No
cutaneous leishmaniasis 21482 that observed for ketoconazole (0.21 μM) [[72]]. Itraconazole has been reported to successfully treat cutaneous leishmaniasis ; however, it was not as effective against Leishmania braziliensis [[53],[73],[74],[75]]. It is noted
sleeping sickness 2482 been suggested that 70 million people in Africa are at risk of human African trypanosomiasis (HAT; sleeping sickness ) [[11]]. Leishmaniasis is caused by various species of Leishmania, while the causative pathogens for
sleeping sickness 37928 desirable drug characteristics with good specificity and low toxicity, and they might be useful in treating sleeping sickness or other protozoan infections [[5]]. When 26-FL is methylated by TbSMT, two carbocations can form as
trypanosomiasis 827 has been focused on using SDM inhibitors to treat neglected tropical diseases such as human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis. Sterol C24-methyltransferase (24-SMT) introduces the C24-methyl
trypanosomiasis 2460 disease [[10]], and it has been suggested that 70 million people in Africa are at risk of human African trypanosomiasis (HAT; sleeping sickness) [[11]]. Leishmaniasis is caused by various species of Leishmania, while the
trypanosomiasis 13368 antifungal azole drugs have reemerged or undergone structural modifications to be used as potential anti- trypanosomiasis drugs. The renaissance of using old antifungal agents for treating or attempting to treat trypanosomiasis
trypanosomiasis 13474 anti-trypanosomiasis drugs. The renaissance of using old antifungal agents for treating or attempting to treat trypanosomiasis was largely driven by large pharmaceutical companies not prepared to invest heavily in neglected diseases

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