Synthesis and Antileishmanial Evaluation of Arylimidamide-Azole Hybrids Containing a Phenoxyalkyl Linker.
Synthesis and Antileishmanial Evaluation of Arylimidamide-Azole Hybrids Containing a Phenoxyalkyl Linker.
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含有苯氧基烷基接头的芳基酰胺二唑 - 疗法的合成和抗抗精神病评估。
DOI：
10.1021/acsinfecdis.0c00855
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发表时间：
2021-07-09
影响因子：
5.3
通讯作者：
Werbovetz KA
中科院分区：
文献类型：
--
作者：
Abdelhameed A;Feng M;Joice AC;Zywot EM;Jin Y;La Rosa C;Liao X;Meeds HL;Kim Y;Li J;McElroy CA;Wang MZ;Werbovetz KA
由于现有药物的局限性，迫切需要新药来治疗内脏利什曼病。在小鼠内脏利什曼病模型中，芳基咪胺类化合物和唑类抗真菌药物都表现出口服活性，因此我们采用分子杂交的方法，用苯氧基烷基键将芳基咪胺类和唑类化合物的基团分开，以期充分利用这两个系列化合物良好的抗利什曼性质。在所合成的目标化合物中，与1，2，4-三氮唑基相比，当连接基长度从2个增加到8个碳时，并且当使用咪唑环作为端基时，对细胞内杜氏利什曼原虫有更强的抗利什曼原虫活性。化合物24c((N-(4-((8-(1H-imidazol-1-yl)octyl)oxy)-2-isopropoxyphenyl))对杜氏钩端螺旋体细胞内无鞭毛虫有一定的抑制作用，其IC50值为0.53μM。与对照组相比，连续五天的治疗导致肝脏寄生虫血症略有下降33%，这表明需要进一步优化这些分子。虽然含咪唑末端基团的高效杂化化合物也是杜诺氏乳杆菌重组细胞色素P51的强抑制剂，但更多的靶点可能在这些化合物的抗利什曼作用中发挥重要作用。
Due to the limitations of existing medications, there is a critical need for new drugs to treat visceral leishmaniasis. Since arylimidamides and antifungal azoles both show oral activity in murine visceral leishmaniasis models, a molecular hybridization approach was employed where arylimidamide and azole groups were separated by phenoxyalkyl linkers in an attempt to capitalize on the favorable antileishmanial properties of both series. Among the target compounds synthesized, greater antileishmanial potency against intracellular Leishmania donovani was observed as the linker length increased from two to eight carbons and when an imidazole ring was employed as the terminal group compared to a 1,2,4-triazole group. Compound 24c (N-(4-((8-(1H-imidazol-1-yl)octyl)oxy)-2-isopropoxyphenyl) picolinimidamide) displayed activity against L. donovani intracellular amastigotes with an IC50 value of 0.53 μM. When tested in a murine visceral leishmaniasis model, compound 24c at a dose of 75 mg/kg/day p.o. for five consecutive days resulted in a modest 33% decrease in liver parasitemia compared to the control group, indicating that further optimization of these molecules is needed. While potent hybrid compounds bearing an imidazole terminal group were also strong inhibitors of recombinant CYP51 from L. donovani as assessed by a fluorescence-based assay, additional targets are likely to play an important role in the antileishmanial action of these compounds.
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影响因子：
3.6
作者：
Gottlieb, HE;Kotlyar, V;Nudelman, A
通讯作者：
Nudelman, A
影响因子：
3.8
作者：
Hailu A;Musa A;Wasunna M;Balasegaram M;Yifru S;Mengistu G;Hurissa Z;Hailu W;Weldegebreal T;Tesfaye S;Makonnen E;Khalil E;Ahmed O;Fadlalla A;El-Hassan A;Raheem M;Mueller M;Koummuki Y;Rashid J;Mbui J;Mucee G;Njoroge S;Manduku V;Musibi A;Mutuma G;Kirui F;Lodenyo H;Mutea D;Kirigi G;Edwards T;Smith P;Muthami L;Royce C;Ellis S;Alobo M;Omollo R;Kesusu J;Owiti R;Kinuthia J;Leishmaniasis East Africa Platform (LEAP) group
通讯作者：
Leishmaniasis East Africa Platform (LEAP) group
影响因子：
7.3
作者：
Harrison JR;Brand S;Smith V;Robinson DA;Thompson S;Smith A;Davies K;Mok N;Torrie LS;Collie I;Hallyburton I;Norval S;Simeons FRC;Stojanovski L;Frearson JA;Brenk R;Wyatt PG;Gilbert IH;Read KD
通讯作者：
Read KD
影响因子：
6.5
作者：
Hargrove, Tatiana Y.;Friggeri, Laura;Lepesheva, Galina I.
通讯作者：
Lepesheva, Galina I.
影响因子：
7.3
作者：
Fotie, Jean;Kaiser, Marcel;Werbovetz, Karl A.
通讯作者：
Werbovetz, Karl A.