Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones.

The influenza virus hemagglutinin (HA) mediates membrane fusion after viral entry by endocytosis. The fusion process requires drastic low pH-induced HA refolding and is prevented by arbidol and tert-butylhydroquinone (TBHQ). We here report a class of superior inhibitors with indole-substituted spirothiazolidinone structure. The most active analogue 5f has an EC50 value against influenza A/H3N2 virus of 1 nM and selectivity index of almost 2000. Resistance data and in silico modeling indicate that 5f combines optimized fitting in the TBHQ/arbidol HA binding pocket with a capability for endosomal accumulation. Both criteria appear relevant to achieve superior inhibitors of HA-mediated fusion.

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, 1H NMR, 13C 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 EC50 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.

Diclofenac-Based Hydrazones and Spirothiazolidinones: Synthesis, Characterization, and Antimicrobial Properties.

We report here the synthesis, structural characterization, and biological evaluation of novel diclofenac-based hydrazone (4a-f) and spirothiazolidinone (5a-f, 6a-f) derivatives designed as potential antimicrobial agents. The compounds were evaluated in vitro for their antiviral activity against a wide spectrum of DNA and RNA viruses. They were further screened in vitro against different strains of bacteria and fungi. The hydrazone derivatives, 4a and 4c-f, were found to be active against herpesviruses (HSV-1, HSV-2, and HSV-1 TK- ), vaccinia virus, and Coxsackie B4 virus, with EC50 values between 6.6 µg/mL and 14.7 µg/mL, and the selectivity index values were greater than 10 for 4a and 4f. The newly synthesized compounds (4-6) were inactive against the bacterial and the fungal strains tested, at levels below 2500, 1250, or 625 µg/mL. Interestingly, the key intermediate 3 with a free hydrazide moiety displayed antifungal properties against Candida albicans and C. parapsilosis at MIC values of 4.88 µg/mL and 78.12 µg/mL, respectively.

Synthesis and antiviral properties of novel indole-based thiosemicarbazides and 4-thiazolidinones.

A novel series of indolylthiosemicarbazides (6a-6g) and their cyclization products, 4-thiazolidinones (7a-7g), have been designed, synthesized and evaluated, in vitro, for their antiviral activity against a wide range of DNA and RNA viruses. Compounds 6a, 6b, 6c and 6d exhibited notable antiviral activity against Coxsackie B4 virus, at EC50 values ranging from 0.4 to 2.1 µg/mL. The selectivity index (ratio of cytotoxic to antivirally effective concentration) values of these compounds were between 9 and 56. Besides, 6b, 6c and 6d also inhibited the replication of two other RNA viruses, Sindbis virus and respiratory syncytial virus, although these EC50 values were higher compared to those noted for Coxsackie B4 virus. The SAR analysis indicated that keeping the free thiosemicarbazide moiety is crucial to obtain this antiviral activity, since the cyclization products (7a-7g) did not produce any antiviral effect.

Indole-based hydrazide-hydrazones and 4-thiazolidinones: synthesis and evaluation as antitubercular and anticancer agents.

A new series of indolylhydrazones (6) and indole-based 4-thiazolidinones (7, 8) have been designed, synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. 4-Thiazolidinone derivatives 7g-7j, 8g, 8h and 8j displayed notable antituberculosis (anti-TB) activity showing 99% inhibition at MIC values ranging from 6.25 to 25.0 µg/ml. Compounds 7g, 7h, 7i, 8h and 8j demonstrated anti-TB activity at concentrations 10-fold lower than those cytotoxic for the mammalian cell lines. The indolylhydrazone derivative 6b has also been evaluated for antiproliferative activity against human cancer cell lines at the National Cancer Institute (USA). Compound 6b showed an interesting anticancer profile against different human tumor-derived cell lines at sub-micromolar concentrations with obvious selectivity toward colon cancer cell line COLO 205.

5-Fluoro-N'-(4-methyl-cyclo-hexyl-idene)-3-phenyl-1H-indole-2-carbohydrazide.

The title compound, C22H22FN3O, crystallized with two independent mol-ecules (A and B) in the asymmetric unit; these are linked by a pair of N-H⋯O hydrogen bonds, forming a pseudo-centrosymmetric dimer with an R (2) 2(10) motif. In addition, a number of C-H⋯π inter-actions are also observed. The 1H-indole ring systems in mol-ecules A and B are essentially planar [maximum deviations of 0.019 (2) and 0.014 (2) Å, respectively] and make dihedral angles of 77.64 (10) and 69.50 (9)°, respectively, with thephenyl rings.

N'-(4-Ethyl-cyclo-hexyl-idene)-5-fluoro-3-phenyl-1H-indole-2-carbohydrazide.

The title compound, C23H24FN3O, crystallizes with two independent mol-ecules (I and II) in the asymmetric unit. These pairs of mol-ecules are linked to each other as N-H⋯O dimers with an R 2 (2)(10) motif. Furthermore, the crystal structure also exhibits C-H⋯π inter-actions. The atoms of the ethyl group in mol-ecule I are disordered over two sites with an occupancy ratio of 0.817 (6):0.183 (6).

5-Chloro-N'-cyclo-hexyl-idene-3-methyl-1H-indole-2-carbohydrazide.

In the title compound, C16H18ClN3O, the cyclo-hexane ring adopts a distorted chair conformation. In the crystal, pairs of mol-ecules are linked by N-H⋯O hydrogen bonds into inversion dimers, forming R 2 (2)(10) ring motifs. These dimers are connected through C-H⋯N hydrogen bonds into chains along the a axis, forming layers parallel to (101).

Synthesis and evaluation of functionalized indoles as antimycobacterial and anticancer agents.

A new series of 5-fluoro-N(2)-(cyclohexylidene)-3-phenyl-1H-indole-2-carbohydrazides (6a-6e) and their cyclization products 5-fluoro-N-(3-oxo-1-thia-4-azaspiro [4.5]dec-4-yl)-3-phenyl-1H-indole-2-carboxamides (7a-7e, 8a-8e) have been synthesized and evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using the Microplate Alamar Blue Assay (MABA). Compounds showed moderate to good inhibitory activity at 6.25 µg/mL. Among them, 7b, 7d, 8b, and 8d were the most potent analogs with an inhibition range of 91-95 %. Additionally, compounds 6a, 7a, 7e, 8a, and 8e were subjected to the National Cancer Institute's (NCI) in vitro disease-oriented antitumor screening to be evaluated for antitumor activity. 8e, the most potent compound examined, displayed broad spectrum antiproliferative activity with particular selectivity against four leukemia cell lines (CCRF-CEM, HL-60 (TB), K-562, and RPMI-8226) with log (10) GI (50) values between -5.68 and -6.09.

5-Chloro-4'-ethyl-3H-spiro-[1,3-benzo-thia-zole-2,1'-cyclo-hexa-ne].

In the title compound, C(14)H(18)ClNS, the 2,3-dihydro-1,3-thia-zole ring adopts an envelope with the S,N-bound C atom at the flap and the cyclo-hexane ring adopts a chair conformation. In the crystal, N-H⋯S hydrogen bonds with C(5) motifs connect the mol-ecules into chains parallel to the c axis.

4'-tert-Butyl-5-chloro-3H-spiro-[1,3-benzothia-zole-2,1'-cyclo-hexa-ne].

In the title compound, C(16)H(22)ClNS, the nine-membered 2,3-dihydro-1,3-benzothia-zole ring system is essentially planar, with a maximum deviation of 0.025 (2) Šfor the N atom. Its plane is almost perpendicular to the main plane of the substituted cyclo-hexane ring, which adopts a chair conformation. In the crystal, the molecules are linked by C-H⋯π inter-actions.

2-[2-(2,6-Dichloro-anilino)phen-yl]-N'-(4-propyl-cyclo-hexyl-idene)acetohydrazide.

The asymmetric unit of the title compound, C(23)H(27)Cl(2)N(3)O, contains two crystallographically independent mol-ecules in which the dihedral angles between the benzene rings are 70.1 (3) and 63.8 (3)°. In each mol-ecule an intra-molecular N-H⋯O hydrogen bond generates an S(7) ring. The atoms of the propyl grouping of one mol-ecule are disordered over two orientations with occupancies of 0.666 (6) and 0.334 (6). The crystal structure is stabilized by N-H⋯O and C-H⋯O hydrogen-bonding inter-actions.

5-Fluoro-N'-[(E)-4-methoxy-benzyl-idene]-3-phenyl-1H-indole-2-carbohydrazide.

In the title mol-ecule, C(23)H(18)FN(3)O(2), the mean plane of the indole system forms dihedral angles of 44.23 (8) and 14.54 (7)°, respectively, with the phenyl and benzene rings. In the crystal, inter-molecular N-H⋯O hydrogen bonds link mol-ecules into two-layer ribbons extended along the b axis. The crystal packing also exhibits weak inter-molecular C-H⋯O, C-H⋯F and C-H⋯π inter-actions.

4-{3-[Hydr-oxy(phen-yl)meth-yl]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-4-yl}benzene-sulfonamide.

In the title compound, C(15)H(14)N(4)O(3)S(2), the hydr-oxy group is disordered over two positions with occupancies of 0.619 (5) and 0.381 (5). The benzene ring attached to the heterocycle makes a dihedral angle of 86.92 (9)° with respect to the best plane through the five-membered ring. The crystal packing is stabilized by inter-molecular O-H⋯O, N-H⋯S, N-H⋯N, C-H⋯O and C-H⋯N hydrogen bonds, and N-H⋯π and C-H⋯π inter-actions.

Synthesis, structure, and antifungal evaluation of some novel 1,2,4-triazolylmercaptoacetylthiosemicarbazide and 1,2,4-triazolylmercaptomethyl-1,3,4-thiadiazole analogs.

Novel 1-[[4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-yl]mercaptoacetyl]-4-alkyl/aryl-3-thiosemicarbazides (5-12) were synthesized by the reaction of 4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-ylmercaptoacetylhydrazide (4) with substituted isothiocyanates. Cyclodehydration of thiosemicarbazides with concentrated sulfuric acid yielded 2-[4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-yl]mercaptomethyl-5-alkyl/arylamino-1,3, 4-thiadiazoles (13-17). The new compounds were evaluated for in vitro antifungal activity using the microdilution method. The tested compounds showed varying degrees of activity against Microsporum gypseum NCPF-580, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, and Candida albicans ATCC 10231 (MIC 8-4 microg/mL).

N'-[(2Z)-3-Allyl-4-oxo-1,3-thia-zolidin-2-yl-idene]-5-fluoro-3-phenyl-1H-indole-2-carbohydrazide.

In the title compound, C(21)H(17)FN(4)O(2)S, the planar indole fused-ring [maximum deviation 0.009 (1) Å] makes dihedral angles of 54.75 (9) and 14.90 (9)°, respectively, with the phenyl ring and the dihydro-thia-zolyl ring. The -CH2CH=CH(2) substituent is disordered over two positions in a 0.51 (1):0.49 (1) ratio. An intra-molecular N-H⋯S hydrogen bond generates an S(5) ring motif. The two independent mol-ecules are linked into a dimer by two N-H⋯O hydrogen bonds, forming an R(2) (2)(10) ring motif. The crystal structure features inter-molecular C-H⋯π and π-π stacking [centroid-centroid distance = 3.679 (1) Å] inter-actions. C-H⋯O and C-H⋯F inter-actions are also present.