VNI (molecule)

VNI is an experimental drug for treating Chagas disease currently being studied at Vanderbilt University. The molecule acts by inhibiting Trypanosoma cruzi sterol 14α-desmethylase activity in vitro. It exhibits no toxicity in mouse cells and unlike the related compounds posaconazole and fluconazole, increasing the dose is not required to maintain anti-parasitic activity.[1][2][3]

VNI
Names
Preferred IUPAC name
N-[(1R)-1-(3,5-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
UNII
  • InChI=1S/C26H19Cl2N5O2/c27-20-10-11-21(22(28)14-20)23(15-33-13-12-29-16-33)30-24(34)17-6-8-19(9-7-17)26-32-31-25(35-26)18-4-2-1-3-5-18/h1-14,16,23H,15H2,(H,30,34)/t23-/m0/s1
    Key: CJPLMXOWZZCYHJ-QHCPKHFHSA-N
  • InChI=1/C26H19Cl2N5O2/c27-20-10-11-21(22(28)14-20)23(15-33-13-12-29-16-33)30-24(34)17-6-8-19(9-7-17)26-32-31-25(35-26)18-4-2-1-3-5-18/h1-14,16,23H,15H2,(H,30,34)/t23-/m0/s1
    Key: CJPLMXOWZZCYHJ-QHCPKHFHBZ
  • c1ccc(cc1)c2nnc(o2)c3ccc(cc3)C(=O)N[C@@H](Cn4ccnc4)c5ccc(cc5Cl)Cl
Properties
C26H19Cl2N5O2
Molar mass 504.37 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

According to the researchers, "VNI cures the acute and chronic forms of Chagas disease in mice, with 100% survival and no observable side effects. Low cost (<$0.10/mg [4]), oral bioavailability, favorable pharmacokinetics, and low toxicity make this compound an exceptional candidate for clinical trials. The efficacy of VNI provides additional compelling support for efficacious antiparasitic treatment of chronic Chagas disease, further validating CYP51 as a viable drug targeting T. cruzi, and it opens a new opportunity for therapeutic cure of patients. Although widespread searches for other new drugs that target T. cruzi are surely being pursued, there are millions of patients with this debilitating illness who need immediate therapy, and VNI or a derivative might fulfill this need."[1]

References
  1. Villalta, F; Dobish, MC; Nde, PN; Kleshchenko, YY; Hargrove, TY; Johnson, CA; Waterman, JN; Johnston, MR; Lepesheva, GI (2013). "VNI Cures Acute and Chronic Experimental Chagas Disease". The Journal of Infectious Diseases. 208 (3): 504–11. doi:10.1093/infdis/jit042. PMC 3698996. PMID 23372180.
  2. Hargrove, TY; Kim, K; de Nazaré Correia Soeiro M; Da Silva, CF; Da Gama Jaen Batista, DD; Batista, MM; Yazlovitskaya, EM; Waterman, MR; Sulikowski, GA; Lepesheva, GI (2012). "CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds". International Journal for Parasitology: Drugs and Drug Resistance. 2: 178–186. doi:10.1016/j.ijpddr.2012.06.001. PMC 3596085. PMID 23504044.
  3. Lepesheva, GI; Park, HW; Hargrove, TY; Vanhollebeke, B; Wawrzak, Z; Harp, JM; Sundaramoorthy, M; Nes, WD; Pays, E; Chaudhuri, M; Villalta, F; Waterman, MR (2010). "Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections". The Journal of Biological Chemistry. 285 (3): 1773–80. doi:10.1074/jbc.M109.067470. PMC 2804335. PMID 19923211.
  4. Dobish, Mark C.; Villalta, Fernando; Waterman, Michael R.; Lepesheva, Galina I.; Johnston, Jeffrey N. (2012). "Organocatalytic, Enantioselective Synthesis of VNI: A Robust Therapeutic Development Platform for Chagas, a Neglected Tropical Disease". Organic Letters. 14 (24): 6322–5. doi:10.1021/ol303092v. PMC 3528807. PMID 23214987.
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