Tetrahydrocarbazoles (THCz) are widespread in numerous indole alkaloids and have been reported since time for exhibiting profound pharmacological potential. Many pharmaceuticals drugs have tetrahydrocarbazole nucleus in their structure e.g. vinca alkaloids (Vincristine, Vinblastine, Vinorelbine), Frovatriptan, (R)-Ramatroban, Ondansetron, etc. that are used in various multifactorial diseases. In this review article, the anticancer potential of tetrahydrocarbazole based derivatives has been covered, enumerating their vast journey from the year 2000 to 2021. Since the last twenty-one years, tetrahydrocarbazoles have been a matter of focus among researchers worldwide, whereby several novel tetrahydrocarbazole derivatives have been synthesized and reported for their anticancer potential against various cancer cell lines. Tetrahydrocarabzole and its derivatives have exhibited profound anticancer potential mediated via various cancer pathways like apoptosis, cell cycle arrest, microtubule inhibition, Nrf2 Modulators, DNA intercalators, pERK and pRb phosphorylation, VEGF (Vascular Endothelial Growth Factor) and TNF-alpha inhibition, TPSO (translocator protein), Histone Deacetylase (HDAC) Inhibitors also discussed. The present review entails the synthesis, SAR studies, and anticancer mechanism of tetrahydrocarbazoles derivatives reported in review literature till date, and would provide a strong database to the medicinal chemist world over in discovering newer potential anticancer agent against various types of cancer diseases.

Thizolidine-2,4-dione on reaction with p-fluorobenzaldehyde in the presence of piperidine and toluene gave (Z)-5-(4-fluorobenzylidine)thiazolidin-2,4-dione (1), which on reaction with carbazole and substituted benzaldehydes in the presence of ethanol yielded (Z)-5-(4-fluorobenzylidene)-3-[(9H-carbazole-9-yl) (2-substituted phenyl)methyl]thiazolidine-2,4-diones (2a-2j). These compounds were screened for their antibacterial activity against Gram-positive bacterial strains such as Bacillus subtilis and Staphylococcus aureus as well as Gram-negative bacterial strains such as Escherichia coli and Pseudomonas aeruginosa. Among the tested compounds 2c and 2d showed significant activity against Gram-positive bacterial strains, and compound 2g was found to be most active against Gram-negative bacterial strains. [GRAPHICS]

Numerous carbazole derivatives were designed by the Chemsketch software followed by 3D optimization. Docking studies were performed using AUTODOCK 4.2.6 software to check their binding interactions with eukaryotic topoisomerase-I, based on the crystal structure of Human Topoisomerse-I-DNA complex (PDB ID: 1A35). Results of docking studies of designed carbazole derivatives were compared on the basis of their minimum binding energy with a well known topoisomerase-I inhibitor i.e. Adriamycin,. Above results were used to find out active compounds and two series of such active compounds i.e. 2-[(4, 5-dihydro-2-substitutedphenyl) imidazol-1-ylamino]-1-(9H-carbazol-9-yl) ethanone (3a-3e) and 2-(9H-carbazol-9-yl)-N'-[{(4-substitutedphenyl)(piperazin-1-yl)} methyl] aceto hydrazide (6a-6e) were synthesized. All the synthesized compounds were characterized by IR, H-1 NMR, C-13 NMR, MASS spectrometry and elemental analysis and also screened for their in vitro anticancer activity against human breast cancer cell line (MCF 7) by sulphorodamine B (SRB) assay method. GI50 was measured by using 10, 20, 40 and 80 mu g/ml concentrations of tested compounds along with the standard i.e. Adriamycin. Results revealed that the tested compounds 3a, 3d, 6c, 6d and 6e were comparable to Adriamycin having GI(50)<10 mu g/ml. Compound 3a and 6c were found to be most active among all the tested compounds.

Numerous carbazole derivatives were designed by the Chemsketch software followed by 3D optimization. Docking studies were performed using AUTODOCK 4.2.6 software to check their binding interactions with eukaryotic topoisomerase-I, based on the crystal structure of Human Topoisomerse-I-DNAcomplex (PDB ID: 1A35). Results of docking studies of designed carbazole derivatives were compared on the basis of their minimum binding energy with a well known topoisomerase-I inhibitor i.e. Rebeccamycin,. Above results were used to find out active compounds and two series of such active compounds i.e. 2-[(4, 5-dihydro-2-substitutedphenyl)imidazol-1-ylamino]-1-(9H-carbazol-9-yl)ethanone (3a-3e) and 2-(9H-carbazol-9-yl)-N'-[{(4-substitutedphenyl)(piperazin-1-yl)}methyl]acetohydrazide (3a-3e) were synthesized. All the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, MASS spectrometry and elemental analysis and also screened for their invitro anticancer activity against human breast cancer cell line (MCF 7) by sulphorodamine B (SRB) assay method. GI50 was measured by using 10, 20, 40 and 80 g/ml concentrations of tested compounds along with the standard i.e. Rebeccamycin. Results revealed that the tested compounds 3c, 3e, and 3a were comparable to Adriamycin having GI50<10g/ml. Compound 3c and 3a were found to be most active among all the tested compounds.

On the basis of pharmacophore model and essential parameters for anticonvulsant activity, a series of 1-[2- (substituted benzylidenhydrazinyl)acetyl]-3-(hydroxyimino)indolin-2-one (4a-4n) were designed and synthesized starting from isatin. The structures of synthesized compounds were confirmed by elemental and spectral analysis. All the compounds were evaluated for their anticonvulsant activity by MES induced seizure model and their neurotoxic effects by rotarod test. Most of the compounds showed moderate to good activity at the dose 30 and 100 mg/kg without neurotoxicity and produced neurotoxicity at 300 mg/kg.

The inhibition property of numerous carbazole derivatives for topoisomerase enzyme was checked by molecular docking which were designed by ChemDraw software followed by 3D optimization. Two series i.e. 2-[(4, 5-dihydro-2-substitutedphenyl) imidazol-1-ylamino]-1-(9H-carbazol-9yl) ethanone (3a-3e) and 2-(9H-carbazol-9-yl)-N'-{[(4-substitutedphenyl) (piperazin-1-yl)]methyl}-acetohydrazide (6a-6e) were found to be potent with minimum binding energy. Above mentioned compounds were synthesized by starting with carbazole and characterized by FTIR, (1) H-NMR, C-13-NMR, MASS spectrometry and elemental analysis. All the synthesized compounds were evaluated for their anticancer activity by SRB assay method against Human Breast Cancer Line (MCF7). All the tested compounds showed moderate to good anticancer activity. Compound 3d and 6c exhibited highest activity toward the inhibition of cancer cell line.

A series of novel 5-((9H-carbazol-9-yl)methyl)-N-((substituted phenyl)(piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-amine (4a-4o) derivatives was synthesized by starting with carbazole which on reaction with ethyl choloroacetate yielded ethyl 2-(9H-carbazole-9-yl)acetate (1), compound (1) on reaction with semicarbazide followed by cyclisation with sulphuric acid gave 5-((9H-carbazole-9-yl)-1,3,4-oxadiazol-2-amine (3) which through Mannich reaction with piperazine and a variety of aromatic aldehydes in the presence of acetic acid yielded the titled compounds (4a-4o). The structures of compounds were characterized by UV, FT-IR, 1H-NMR, MS spectral studies and elemental analysis. All the derivatives were evaluated for their antibacterial, antifungal and anticancer activities. Among the tested compounds 4a, 4d, 4e and 4n exhibited significant antibacterial and antifungal activity while the compounds 4a, 4d, 4k and 4n were found to be active on Human Breast Cancer Cell Line i.e. MCF7.

Benzodiazepines and their derivatives were reported to have wide biological activities and were synthesized by the reaction between substituted benzaldehydes and substituted ketones in presence of sodium hydroxide to afford chalcones and further reaction between 1, 2-diamine under smooth condensation with chalcones in presence of glacial acetic acid afforded a new class of 1, 5-benzodiazepines in good yield. 2, 4-disubstituted 1, 5-benzodiazepine derivatives (1B-19B) were synthesized by microwave and conventional methods. The synthesized compounds were evaluated for their antibacterial, antifungal, anthelmintic and cytotoxic activity. The chemical structures of the newly synthesized compounds have been confirmed by IR, 1H-NMR, MASS spectral data and elemental analysis. All the synthesized substituted benzodiazepines have shown good antimicrobial activity, moderate to good anthelmintic activity and possessed significant cytotoxic activity.

In present study (5-(5-chloro-1,3-diphenyl-1H-pyrazole-4-yl)-3-(substitutedphenyl)-1H-pyrazol-1-yl)(pyridine- 4-yl)methanone (4a-4o)were synthesized by starting with acetophenone and phenylhydrazine resulting in the formation of acetophenonephenylhydrazone(1). Compound (1) on Vilsmeier-Haack reaction yielded 5-chloro-1,3-diphenyl- 1 H-pyrazole-4-carbaldehyde (2), which on condensation with substituted acetophenone gave substituted arylidenepyrazoles(3a-3o) followed by the reaction with isoniazid yielded the titled compounds (4a-4o). All the newly synthesized pyrazolederivatives were characterized by UV, FTIR, 1H NMR, MASS spectrometry and elemental analysis. All the newly synthesized derivatives were also evaluated for their antitubercular activity against Mycobacterium tuberclosis H 37 Rv using agar dilution method as well as for anticancer activity against MCF7 (Human breast cancer) cells by SRB assay.

Carbazole on reaction with chloroacetyl chloride afforded N9-(chloroacetyl)-carbazole (1) which on treatment with hydrazine hydrate has yielded N9-(hydrazinoacetyl)-carbazole (2), Condensation of (2) with various aromatic aldehydes afforded N9-(arylidene hydrazinoacetyl)-carbazoles (3a-3k), which on cycloaddition with isatin in the presense of ammonium acetate yielded 1-Carbazole-9-yl-2-(substitutedphenyl)-1,4-dihydroimidazo[4,5-b]indole 1- ylamino)-ethanone (4a-4k). All the synthesized compounds were evaluated for their antibacterial, antifungal, and anticancer activity. The structures of the newly synthesized compounds were confirmed by FTIR, 1H NMR, MASS spectral data and elemental analysis. Compounds were screened for in-vitro antibacterial activity against the representative panel of two gram positive bacterial strains like Staphylococcus aureus and Bacillus subtilis and two gram negative bacterial strain like Pseudomonas aeruginosa and Escherichia coli and antifungal activity by inhibitory action against two fungal strains like Candida albicans and Aspergillus niger. The synthesized compounds were also evaluated for their anticancer activity by SRB assay method on A549 cell lines. All the newly synthesized substituted carbazoles have shown moderate to good antibacterial, antifungal and anticancer activity.

Substituted primary aromatic amines on diazotization gives diazonium salt which on reaction with various piperazine derivatives get converted into diazotized product 3a-e, 4a-e and 5b-c. The structures of the newly synthesized piperazine derivatives were accomplished through IR, H-1 NMR and mass spectral data. All derivatives showed moderate to good anthelmintic activity against Phaeritima posthuma species of earthworm at the concentration of 75.0 mg/mL, when compared with piperazine citrate as reference compound. Among all the synthesized compounds, the compound 2-(4-methylpiperazin-1-yl)-1-phenyldiazene (4a), 2-(4-methylpiperazin-1-yl)-1-(4-nitrophenyl)diazene (4b) and 1-(4-chlorophenyl)-2-(4-methylpiperazin-1-yl)diazene (4c) were found to be most potent towards anthelmintic activity.

The reaction of bromoanthranilic acid with benzoyl chloride gave oxazine-4-one derivative (1) which on reaction with formamide gave quinazolin-4-(3H)-one derivative (2). The esterified product of quinazolin-4-(3H)-one derivative (3) on reaction with hydrazine hydrate gave (7-bromo-2-phenylquinazolin-4-yloxy) acetohydrazide (4) which on reaction with substituted benzaldehydes yielded the final series of N'-(substituted benzylidene)-2-(7-bromo-2-phenylquinazolin-4-yloxy) acetohydrazides (5a-5k). The structures of the synthesized compounds have been established by spectroscopic and elemental analysis. All the newly synthesized quinazoline derivatives were screened for antibacterial and antifungal activity.

Using silica gel as solid support tetraaryl imidazoles (2a-h) have been synthesized and characterized by FTIR, H-1 NMR, Mass spectroscopy and elemental analysis. These compounds were screened for antibacterial activity against S. aureus, B. subtilis, E. coli, P aeruginosa, K. pneumoniae and short term anticancer activity against Ehrlich's Ascites Carcinoma (EAC) cell lines.