ARKIVOC 2006 (i) 109-118
Synthesis and primary antiviral activity evaluation of 3-hydrazono-5-nitro-2-indolinone derivatives Nalan Terzioğlu *a, Nilgün Karalı a, Aysel Gürsoy a, Christophe Pannecouque b, Pieter Leysen b, Jan Paeshuyse b, Johan Neyts b, and Erik De Clercq b a
Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116, Istanbul, Turkey b Rega Institue of Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium E-mail: email@example.com
Abstract A series of 5-nitro-3-[(5-nonsubstituted/methyl-4-thiazolidinone-2-ylidene)hydrazono]-1H-2indolinones (3a-j and 4a-h) was synthesized by cyclization of 5-nitro-1H-indole-2,3-dione-3thiosemicarbazones (1a-k) with ethyl bromoacetate or ethyl 2-bromopropionate. The primary antiviral activities of the new hydrazonoindolinone derivatives, the previously reported 5-nitro1H-indole-2,3-dione-3-thiosemicarbazones (1a-k) and 1-morpholino/piperidinomethyl-5-nitroindole-2,3-dione-3-thiosemicarbazones (2a-l) were evaluated against some pathogenic viruses in the Rega Institue for Medical Research, Belgium. Among the tested compounds, 1c, 2b and 3b afforded some weak activity against the yellow fever virus (YFV) in vero cells, whereas compounds 2b, 3a, 3f, 4e and 4f inhibited the growth of bovine viral diarrhea virus (BVDV) in MDBK CODA cells. Keywords: 1H-2-Indolinones, 4-thiazolidinones, antiviral activity
Isatin (1H-indole-2,3-dione) is a versatile lead molecule for designing potential antiviral agents. Several authors found that isatin-β-thiosemicarbazone (1H-indole-2,3-dione-3thiosemicarbazone) and its N-Mannich bases were active against various viruses1. The first clinically approved antiviral agent, N-methylisatin-β-thiosemicarbazone (methisazone, I), and isatin-β-thiosemicarbazone (II) are active against poxviruses2. Antiviral properties of certain thiourea and semicarbazone derivatives have been reported in which the antiviral effect is attributed to the presence of an intact NHC(=S)NH grouping and NHC(=O)NH grouping3. The cyclic urea derivative (III), as a replicase inhibitor specific to the bovine viral diarrhea virus (BVDV)4 has been recently identified. On the other hand, some original 4-thiazolidones are
ARKIVOC 2006 (i) 109-118
undergoing different stages of clinical trials as potential antimicrobial, antiviral, anticancer and thrombolytic drugs. It has been reported that members of a series of 2,3-diaryl-1,3-thiazolidin-4ones were highly effective in inhibiting the cytopathic effect of HIV-1 in human T-lymphocyte cells5. The 2-thioxo-4-thiazolidone derivative, epalrestat (IV) is a highly active aldose reductase inhibitor (Figure 1). S N NH O N R1
R1= CH3, R2= H R1=R2= H
R2 N R
N N N N O N H
O COOH S
Figure 1 In view of these observations, we report here the synthesis of the new 5-nitro-3-[(5nonsubstituted/ methyl-4-thiazolidinone-2-ylidene)hydrazono]-1H-2-indolinones (3 and 4) and evaluation of in vitro antiviral activity of these new compounds and some of the previously reported 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones (1) and 1-morpholino/ piperidinomethyl-5-nitro-indole-2,3-dione-3-thiosemicarbazones (2).
Results and Discussion
Treatment of ethyl bromoacetate or ethyl 2-bromopropionate with 5-nitro-1H-indole-2,3-dione3-thiosemicarbazone 1a-k in anhydrous ethanolic medium furnished the corresponding 5-nitro-3[(5-nonsubstituted/methyl-4-thiazolidinone-2-ylidene)hydrazono]-1H-2-indolinones (3a-j and 4a-h) (Scheme 1). The structures of 3 and 4 were confirmed by analytical and spectral data (IR, 1H NMR, 13C NMR and EIMS) (Table 1). In the IR spectra of 3 and 4, the C=S bands disappeared, a new C=O band (1756-1734 cm-1) indicative of the thiazolidinone structure appeared in addition to the lactam C=O stretching (1705-1689 cm-1)6. 1H-NMR spectra of 3 and 4 did not...
References: 464. (c) Balzarini, J.; Naesens, L.; Slachmuylders, J.; Niphuis, H.; Rosenberg, I.; Holy, A.; Schellekens, H.; De Clercq, E. AIDS 1991, 5, 21. (d) Neyts, J.; Meerbach, A.; McKenna, P.; De Clercq, E. Antiviral Res. 1996, 30, 125.
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