Design, synthesis, antitubercular and antiviral properties of new spirocyclic indole derivatives

Abstract

A series of indole-based spirothiazolidinones have been designed, synthesized and evaluated, in vitro, for their antitubercular, antiviral, antibacterial, and antifungal activities. The structures of the new compounds were established by IR, 1 H NMR, 13 C NMR (proton decoupled, APT, and DEPT), electrospray ionization mass spectrometry, and microanalysis. Compounds bearing a phenyl substituent at position 8 of the spiro ring, exhibited significant antitubercular activity against Mycobacterium tuberculosis H37Rv ATCC 27294 at concentrations of 3.9 and 7.8 µM. Still, some of the tested compounds displayed activity on mycobacteria with MIC values of 16 and 31 µM. Four of the indole-spirothiazolidinone derivatives were found to be moderately active against Punta Toro virus, yellow fever virus or Sindbis virus in Vero cells. The antiviral EC 50 values were in the range of 1.9-12 µM and the selectivity index (ratio of cytotoxic to antivirally effective concentration) was above 10 in some cases. The most potent effect was seen with the compound that is methylated at positions 2 and 8 of the spirothiazolidinone system. Graphic abstract

A brief review of the biological potential of indole derivatives

“…The range of IC 50 values was 1.9-12 μM. Compound 5-chloro-N-((2S,5S, 8R)-2,8-dimethyl-3-oxo-1-thia-4-azaspiro [4.5]decan-4yl)-3-phenyl-1H-indole-2-carboxamide (20) was the most active [12].…”

“…naphthols through Mannich bases and tested against different viruses and compound methyl 1-((1H-indol-3yl)methyl)-2-naphthoate (7) showed significant activity against Yellow Fever Virus (YFV), Bovine viral diarrhea virus (BVDV), Human immunodeficiency virus-1 (HIV-1), and Respiratory syncytial virus (RSV) [7]. 5-Nitro-3-[(5-nonsubstituted/methyl-4-thiazolidinone-2ylidene) hydrazono]-1H-2-indolinones were prepared and tested for antiviral activities by Terzioğlu et al Compounds (Z)-4-allyl-1-(1-(morpholinomethyl)-5-nitro-2-oxoindolin-3-ylidene)thiosemicarbazide (9), (3Z,3E)-3-(2-(3-ethyl-4oxothiazolidin-2-ylidene)hydrazono)-5-nitroindolin-2-one (10), (3Z,3E)-5-nitro-3-(2-(4-oxo-3-phenylthiazolidin-2-ylidene)hydrazono)indolin-2-one (11), (3Z,3E)-3-(2-(3-(4-bromophenyl)-5-methyl-4-oxothiazolidin-2-ylidene)hydrazono)-5-nitroindolin-2-one (12) and (3Z,3E)-3-(2-(3-(4chlorophenyl)-5-methyl-4-oxothiazolidin-2-ylidene)hydrazono)-5-nitroindolin-2-one (13) prevented the development of bovine viral diarrhea virus in cells [9]. 7-Ethoxy-1-methyl-4, 9-dihydro-3H-pyrido [3, 4-b]indole derivatives were reported as anti-Herpes Simplex virus-1(HSV-1) compounds by El-sawy et al and derivatives ethyl (17) possessed considerable antiviral activity with IC 50 ranged between 5 and 6 μg/ml and substantial therapeutic indices (TI) of 80 and 83 were recorded [10].…”

New spirothiazolidinone derivatives: Synthesis and antiviral evaluation

“…Target compounds (3a-f, 4a-f) were obtained by means of a one-pot three-component cyclocondensation reaction. [18,22,23] The refluxing of hydrazines and an appropriate cyclohexanone with 2-sulfanylpropanoic acid in toluene using a Dean-Stark apparatus for 6-8 h, gave the desired spirothiazolidinones. All compounds were characterized by IR, 1 H NMR spectra, and elemental analysis.…”

Synthesis of new N‐(3‐oxo‐1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)pyridine‐3‐carboxamide derivatives and evaluation of their anti‐influenza virus and antitubercular activities

“…Effective inhibition of bacterial growth was noted for a few analogs bearing a 6-phenyl substituted imidazo [2,1-b]thiazole residue (Figure 2a) [15,16] and 3-phenyl substituted indole residue (Figure 2b). [17][18][19] Imidazo [2,1-b]thiazolesubstituted spirothiazolidinones have been reported to inhibit the growth of 50% of M. tuberculosis H37Rv at concentrations ranging from 0.76 to 4.5 μg/ml. Among the previously reported indolederived spirothiazolidinones, compounds bearing phenyl substituent at the 8-position of the spiro ring and a chlorine atom at the 5-position of the indole ring were found to be the most potent analogs.…”

“…These derivatives displayed significant activity on mycobacteria with minimum inhibitory concentration (MIC) values (the lowest concentration of compound that inhibited 100% of mycobacterial growth in the culture) of 3.9 and 7.8 μM. [19] In the present study, we examined the influence of introducing the pyridinecarbohydrazide moiety. This structure is present in the first-ever approved antituberculosis drug, isoniazid (INH).…”