Polymerization Inhibitory Activity Research Articles

Synthesis and Selective Anticancer Activity Evaluation of 2-phenylacrylonitrile Derivatives as Tubulin Inhibitors.

This study aimed at synthesizing 13 series of novel derivatives with 2-phenylacrylonitrile, evaluating antitumor activity both in vivo and in vitro, and obtaining novel tubulin inhibitors. The 13 series of 2-phenylacrylonitrile derivatives were synthesized by Knoevenagel condensation and the anti-proliferative activities were determined by MTT assay. The cell cycle and apoptosis were analyzed by flow cytometer. Quantitative cell migration was performed using 24-well Boyden chambers. The proteins were detected by western blotting. in vitro kinetics of microtubule assembly was measured using ELISA kit for Human β-tubulin (TUBB). Molecular docking was done by Discovery Studio (DS) 2017 Client online tool. Among the derivatives, compound 1g2a possessed strong inhibitory activity against HCT116 (IC50 = 5.9 nM) and BEL-7402 (IC50 = 7.8 nM) cells. Compound 1g2a exhibited better selective antiproliferative activities and specificities than all the positive control drugs, including taxol. Compound 1g2a inhibited proliferation of HCT116 and BEL-7402 cells by arresting them in the G2/M phase of the cell cycle, inhibited the migration of HCT116 and BEL-7402 cells and the formation of cell colonies. Compound 1g2a showed excellent tubulin polymerization inhibitory activity on HCT116 and BEL-7402 cells. The results of molecular docking analyses showed that 1g2a may inhibit tubulin to exert anticancer effects. Compound 1g2a shows outstanding antitumor activity both in vivo and in vitro and has the potential to be further developed into a highly effective antitumor agent with little toxicity to normal tissues.

Anthraquinones from the roots of Morinda scabrida Craib exhibit antiproliferative activity against A549 lung cancer cells and antitubulin polymerization

Six anthraquinones were isolated from Morinda scabrida Craib, an unexplored species of Morinda found in the tropical forest of Thailand. All six anthraquinones showed cytotoxicity against A549 lung cancer cells, with the most active compound, nordamnacanthal (MS01), exhibiting the IC50 value of 16.3 ± 2.5 μM. The cytotoxic effect was dose-dependent and led to cell morphological changes characteristic of apoptosis. In addition, flow cytometric analysis showed dose-dependent apoptosis induction and the G2/M phase cell cycle arrest, which was in agreement with the tubulin polymerization inhibitory activity of MS01. Molecular docking analysis illustrated the binding between MS01 and the α/β-tubulin heterodimer at the colchicine binding site, and UV–visible absorption spectroscopy revealed the DNA binding capacity of MS01.

Design, synthesis and biological evaluation of novel dihydroquinolin-4(1H)-one derivatives as novel tubulin polymerization inhibitors

A series of novel dihydroquinolin-4(1H)-one derivatives targeting colchicine binding site on tubulin were designed, synthesized and evaluated as anticancer agents. The most potent compound 6t showed remarkable antiproliferative activities against four cancer cell lines with IC50 values among 0.003–0.024 μM and tubulin polymerization inhibitory activity (IC50 = 3.06 μM). Further mechanism studies revealed that compound 6t could induce K562 cells apoptosis and arrest at the G2/M phase. Meanwhile, 6t significantly inhibited migration and invasion of MDA-MB-231 cells, and disrupted the angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro. In addition, compound 6t inhibited tumor growth in H22 allograft tumor model with a tumor growth inhibition (TGI) rate of 63.3 % (i.v., 20 mg/kg per day) without obvious toxicity. Collectively, these results indicated that compound 6t was a novel tubulin polymerization inhibitor with potent anticancer properties in vitro and in vivo.

Design, synthesis and tubulin polymerization inhibition activity of newly synthesized hydrazone-linked to combretastatin analogues as potential anticancer agents

A new series of hydrazone derivatives were synthesized by varying the active part (hydrazide group) of cis-vinyl amide derivatives, characterized by 1H NMR, 13C NMR spectral data and screened for their cytotoxic activity against MCF-7 breast cancer cell line. Results indicated that compounds 3 g, 3k and 4 were potent cytotoxic agents (IC50 = 4.02–5.36 μM) relative to CA-4 as a reference compound. The most active hydrazinyl compounds were further evaluated for the β-tubulin inhibition activity. Cellular cycle analysis of the inhibitory effect of N-(furan-2-ylmethylene)hydrazinyl 4 on each phase of the cell cycle of breast adenocarcinoma MCF-7 cells was investigated using flow cytometric analysis. Test compound elicited cellular cycle arrest at G2/M phase. Annexin V dual staining analysis results revealed that treatment of MCF-7 cells with N-(furan-2-ylmethylene)hydrazinyl 4 increase the percentage of apoptosis compared to negative untreated control. Besides, N-(furan-2-ylmethylene)hydrazinyl 4 induced apoptosis via decreased the level of mitochondrial membrane potential relative to untreated control cells as revealed by flow cytometry analysis. Moreover, molecular modeling investigations were conducted to clarify the manner in which the most potent compound binds within the tubulin's colchicine-binding pocket, thereby elucidating the reasons behind its exceptional cytotoxicity and its superior ability to inhibit tubulin when compared to CA-4.

Steroids from Toona sureni-derived Endophytic Fungi Stemphylium sp. MAFF 241962 and Their Heme Polymerization Inhibition Activity

Abstract Antimalarial drug resistance is a major cause of the increasing incidence of malaria worldwide, necessitating an urgent demand for the development of new antimalarial drugs. However, the availability of bioactive natural compounds derived from plants is often limited. To address this issue, continuous exploration of bioactive secondary metabolites from endophytic fungi derived from medicinal plants has been recognized as a viable alternative. Therefore, this research aimed to isolate and characterize three ergosteroids, namely isocyathisterol (1), ergosterol-5,8-peroxide (3), cerevisterol (4), and a phytosterol, β-sitosterol (2), from the rice cultures of endophytic fungus Stemphylium sp. MAFF 241962, derived from Toona sureni. Endophytic fungi species were determined using molecular analysis of the internal transcribed region (ITS) of the ribosomal DNA. After comparing the sequence data to the NCBI database using BLAST, endophytic fungi were identified as Stemphylium sp. 241962 with 100% similarity. The chemical structures were elucidated using spectroscopic methods, including 1D and 2D NMR. Antimalarial activities of compounds 1-4 were evaluated using heme polymerization inhibition activity (HPIA) method. The results showed moderate inhibition activities with IC50 values of 7.70 ± 0.11, 9.48 ± 0.09, 7.88 ± 0.10, and 8.36 ± 0.56 mg/mL, respectively, compared to positive control chloroquine diphosphate with IC50 values of 1.59 ± 0.03 mg/mL. Keywords: Steroid, Stemphylium sp., Toona sureni, Antimalarial activity, Heme polymerization inhibition

Discovery of novel 2-(trifluoromethyl)quinolin-4-amine derivatives as potent antitumor agents with microtubule polymerization inhibitory activity

In this work, a series of 2-(trifluoromethyl)quinolin-4-amine derivatives were designed and synthesized through structural optimization strategy as a microtubule-targeted agents (MTAs) and their cytotoxicity activity against PC3, K562 and HeLa cell lines were evaluated. The half maximal inhibitory concentration (IC50) of 5e, 5f, and 5o suggested that their potency of anti-proliferative activities against HeLa cell lines were better than the combretastatin A-4. Compound 5e showed the higher anti-proliferative activity against PC3, K562 and HeLa in vitro with IC50 values of 0.49 µM, 0.08 µM and 0.01 µM, respectively. Further mechanism study indicated that the representative compound 5e was new class of tubulin inhibitors by EBI competition assay and tubulin polymerization assays, it is similar to colchicine. Immunofluorescence staining revealed that compound 5e apparently disrupted tubulin network in HeLa cells, and compound 5e arrested HeLa cells at the G2/M phase and induced cells apoptosis in a dose-dependent manner. Molecular docking results illustrated that the hydrogen bonds of represented compounds reinforced the interactions in the pocket of colchicine binding site. Preliminary results suggested that 5e deserves further research as a promising tubulin inhibitor for the development of anticancer agents.

New steroid produced by Periconia pseudobyssoides K5 isolated from Toona sureni (Meliaceae) and its heme polymerization inhibition activity

A new ergostane-type steroid named (22E)-3α,6α,9α-ergosta-7,22-diene-3,6,9-triol (1), along with six known steroids 5α,8α-epidioxy-24-ethyl-cholest-6-en-3β-ol (2), ergosterol-5,8-peroxide (3), cerevisterol (4), isocyathisterol (5), 6β-hydroxystigmast-4-en-3-one (6), 6β-hydroxy-4-campesten-3-one (7), were isolated from the fermented unpolished rice media by Periconia pseudobyssoides K5 (Periconiaceae), an endophytic fungus from medicinal plant Toona sureni (Meliaceae). The fermentation takes at 28 ± 2 °C for 30 days. The structure of new steroid (1) was elucidated by extensive spectroscopic measurements (IR, HR-ESI-TOFMS, and 1D and 2D NMR) analyses. The isolated compounds (1–7) were evaluated for heme polymerization inhibition assay (HPIA). The IC50 HPIA value of 1 is 8.24 ± 0.03 mg/ml.

Benzotriazole Substituted 2-Phenylquinazolines as Anticancer Agents: Synthesis, Screening, Antiproliferative and Tubulin Polymerization Inhibition Activity.

Development of anticancer agents targeting tubulin protein. Tubulin protein is being explored as an important target for anticancer drug development. Ligands binding to the colchicine binding site of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in the G2/M phase. Synthesis and screening of benzotriazole-substituted 2-phenyl quinazolines as potential anticancer agents. A series of benzotriazole-substituted quinazoline derivatives have been synthesized and evaluated against human MCF-7 (breast), HeLa (cervical) and HT-29 (colon) cancer cell lines using standard MTT assays. ARV-2 with IC50 values of 3.16 μM, 5.31 μM, 10.6 μM against MCF-7, HELA and HT29 cell lines, respectively displayed the most potent antiproliferative activities in the series while all the compounds were found non-toxic against HEK293 (normal cells). In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, ARV-2 and ARV-3 were found to induce mitochondria-mediated apoptosis. The benzotriazole-substituted 2-phenyl quinazolines have the potential to be developed as potent anticancer agents.

Diketopiperazine Cyclo-(S-Pro-R-Leu) Produced by Periconia pseudobyssoides K5 Isolated from Toona sureni (Meliaceae) and its Heme Polymerization Inhibition Activity

Fungi endophytes are living microorganisms colonizing inside the internal tissue of a plant and provide ecological benefits for their host. Endophytes provide various metabolites for plant adaptation toward biotic and abiotic stresses and have tremendous pharmacological activities. Toona sureni (T. sureni) (Meliaceae) belongs to the Toona genera and is reported to have antimalarial activity. To determine the compounds produced by the endophytic fungus from this plant, we isolated a compound from Periconia pseudobyssoides (P. pseudobyssoides) K5 endophytes from the stem bark of T. sureni. Diketopiperazine cyclo-(S-Pro-R-Leu), a non-ribosomal peptide, was isolated from brown rice fermented at 28 ± 2 ℃ for 30 days. The structure was determined by spectroscopic methods including fourier-transform infrared spectroscopy, mass spectrometry, and 1D and 2D nuclear magnetic resonance techniques. This compound was evaluated for heme polymerization inhibition activity (HPIA) with an IC50 value of 9.89 ± 0.24 mmol/L compared with positive control chloroquine phosphate with an IC50 value of 3.08 ± 0.58 mmol/L. This compound has been categorized as having low activity three times lower than positive control chloroquine phosphate. This information provides new leads about the compound diketopiperazine cyclo-(S-Pro-R-Leu) produced by P. pseudobyssoides K5 endophytes having low activity in inhibiting heme polymerization. In the future, to explore the potency of this compound as antimalarial agent, the other antimalarial test such as lactate dehydrogenase assay might be useful.

New Schiff Base–TMB Hybrids: Design, Synthesis and Antiproliferative Investigation as Potential Anticancer Agents

The structural symmetry or asymmetry of organic compounds is one of the most fundamental characteristics. Z-geometrical isomers are promiscuous and kinetically preferred structures with a plethora of biological activities. A new series of hybrid molecules containing Schiff base and 3,4,5-trimethoxybenzamide moieties were synthesized from the starting material ethyl acrylate ester derivative (Z)-1 and structurally confirmed by elemental microanalysis, 1H-NMR, and 13C-NMR spectroscopic studies. The in vitro cytotoxic activity of the target hybrids was tested against the MCF-7 breast cancer line compared with colchicine as the reference compound. Most of the newly synthesized hybrids showed good growth inhibition activity against the MCF-7 cells compared to the reference substance. The results of the β-tubulin polymerization inhibition activity assay showed that the p-vanillin Schiff base 4g displayed good inhibition activity. In addition, p-vanillin Schiff base 4g exhibited antiproliferative activity over the MCF-7 cells by cellular cycle blockade at the G2/M phase and it is a potent apoptotic agent. qRT-PCR analysis showed that Schiff base 4g boosted the mRNA expression of the p53 and Bax levels while lowering the expression of the Bcl-2 level.

Influence of Eugenol and Its Novel Methacrylated Derivative on the Polymerization Degree of Resin-Based Composites.

The aim of this work was to assess the limiting rate of eugenol (Eg) and eugenyl-glycidyl methacrylate (EgGMA) at which the ideal degree of conversion (DC) of resin composites is achieved. For this, two series of experimental composites, containing, besides reinforcing silica and a photo-initiator system, either EgGMA or Eg molecules at 0-6.8 wt% per resin matrix, principally consisting of urethane dimethacrylate (50 wt% per composite), were prepared and denoted as UGx and UEx, where x refers to the EgGMA or Eg wt% in the composite, respectively. Disc-shaped specimens (5 × 1 mm) were fabricated, photocured for 60 s, and analyzed for their Fourier transform infrared spectra before and after curing. The results revealed concentration-dependent DC, increased from 56.70% (control; UG0 = UE0) to 63.87% and 65.06% for UG3.4 and UE0.4, respectively, then dramatically decreased with the concentration increase. The insufficiency in DC due to EgGMA and Eg incorporation, i.e., DC below the suggested clinical limit (>55%), was observed beyond UG3.4 and UE0.8. The mechanism behind such inhibition is still not fully determined; however, radicals generated by Eg may drive its free radical polymerization inhibitory activity, while the steric hindrance and reactivity of EgGMA express its traced effect at high percentages. Therefore, while Eg is a severe inhibitor for radical polymerization, EgGMA is safer and can be used to benefit resin-based composites when used at a low percentage per resin.

Exploration of cytotoxic potential and tubulin polymerization inhibition activity of cis-stilbene-1,2,3-triazole congeners.

To scrutinize cis-stilbene based molecules with potential anticancer and tubulin polymerization inhibition activity, a new series of cis-stilbene-1,2,3-triazole congeners was designed and synthesized via a click chemistry protocol. The cytotoxicity of these compounds 9a-j and 10a-j was screened against lung, breast, skin and colorectal cancer cell lines. Based on the results of MTT assay, we further evaluated the selectivity index of the most active compound 9j (IC50 3.25 ± 1.04 μM on HCT-116) by comparing its IC50 value (72.24 ± 1.20 μM) to that of the normal human cell line. Further, to confirm apoptotic cell death, cell morphology and staining studies (AO/EB, DAPI and Annexin V/PI) were carried out. The outcomes of studies showed apoptotic features like change in cell shape, cornering of nuclei, micronuclei formation, fragmented, bright, horseshoe-shaped nuclei, etc. Moreover, active compound 9j displayed G2/M phase cell cycle arrest with significant tubulin polymerization inhibition activity with an IC50 value of 4.51 μM. Additionally, in silico ADMET, molecular docking and molecular dynamic studies of 9j with 3E22 protein proved the binding of the compound at the colchicine binding site of tubulin.

THE POTENTIAL ANTIMALARIAL DRUG OF ARYL AMINO ALCOHOL DERIVATIVES FROM EUGENOL: SYNTHESIS, in-vitro AND in-silico ANALYSIS OF BIOACTIVITY

Malaria is a significant cause of death in numerous countries, and the discovery of effective drugs is crucial. In this research, a new method was employed to synthesize a derivative of aryl amino alcohol using eugenol. Initially, an epoxide compound called 2-methoxy-4-(oxiran-2-ylmethyl) phenol was synthesized from eugenol by reacting it with peroxyacetic acid in dichloromethane. Subsequently, the epoxide compound was subjected to a reaction with various amine compounds, including aniline, naphthylamine, and diphenylamine for 10 minutes under 100 W microwave conditions, resulting in the production of three derivative compounds of aryl amino alcohol. The antimalarial activity of these synthesized compounds was assessed in-vitro through an assay called heme polymerization inhibition activity (HPIA). Additionally, an in-silico analysis was conducted to evaluate the bioactivity of the three aryl amino alcohol derivatives by performing molecular docking with the Plasmepsin II enzyme. The identification of the products were determined using Fourier Transform Infrared (FTIR) spectrophotometry, proton nuclear magnetic resonance (1HNMR) spectrometry, and Electrospray ionization-Mass Spectrometry (ESI-MS). The research successfully obtained three aryl amino alcohol derivatives: 2-hydroxy-3-(phenylamino) propyl)-2-methoxyphenol, 4-(2-hydroxy-3- (naphthalene-1-ylamino) propyl)-2-methoxyphenol, and 4-(2-hydroxy-3-(diphenylamine)-2-methoxy phenol. All the synthesized compounds demonstrated lower IC50 values compared to chloroquine, indicating their potential as antimalarial drugs. Molecular docking studies revealed that these aryl amino alcohol derivatives effectively inhibited the activity of the Plasmepsin II enzyme

Design, synthesis and antiproliferative screening of newly synthesized acrylate derivatives as potential anticancer agents.

A new series of acrylic acid and acrylate ester derivatives as modified analogs of tubulin polymerization inhibitors were designed and synthesized. The antiproliferative activity of the constructed molecules was investigated against MCF-7 breast carcinoma cells using CA-4 as positive molecule. Methyl acrylate ester 6e emerged as the most potent cytotoxic agent against MCF-7 cells, with an IC50 value of 2.57 ± 0.16 μM. Also, methyl acrylate ester molecule 6e showed good β-tubulin polymerization inhibition activity. Cellular cycle analysis showed that compound 6e can arrest MCF-7 cells at the G2/M phase. In addition, this compound produced a significant increase in apoptotic power as compared to control untreated MCF-7 cells. Furthermore, the effect of acrylate ester 6e on the gene expression levels of p53, Bax and Bcl-2 was investigated. This molecule increased the expression levels of both p53 and Bax, and decreased the gene expression level of Bcl-2 as compared to control untreated MCF-7 carcinoma cells.

Discovery of Novel Acridane-Based Tubulin Polymerization Inhibitors with Anticancer and Potential Immunomodulatory Effects.

A series of novel acridane-based tubulin polymerization inhibitors were designed, synthesized, and bioevaluated as anticancer agents. The most potent compound NT-6 exhibited high tubulin polymerization inhibitory activity (IC50 = 1.5 μM) and remarkable antiproliferative potency against four cancer cell lines with an average IC50 of 30 nM, better than colchicine and the hit compound 1f (IC50 of 65 and 126 nM, respectively). In addition, NT-6 (10 mg/kg) exerted excellent antitumor efficacy in a melanoma tumor model with a tumor growth inhibition (TGI) of 65.1% without apparent toxicity. Importantly, the combination of NT-6 with a small-molecule PD-L1 inhibitor NP-19 decreased tumor burden significantly (TGI% = 77.6%). Moreover, the combination of NT-6 with NP-19 enhanced the antitumor immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of antitumor CD8+ effector T cells in tumor tissues. Collectively, NT-6 represents a novel tubulin polymerization inhibitor with immunopotentiating effects.

Discovery of pyrazole-carbohydrazide with indole moiety as tubulin polymerization inhibitors and anti-tumor candidates.

In this work, a series of indole-containing pyrazole-carbohydrazide derivatives A1-A25 were synthesized, and their biological activity on tubulin polymerization inhibition and mitotic catastrophe was evaluated. For introducing indole group to CA-4 pattern, the carbohydrazide linker was used for the first time. As the top hit, A18 suggested notable antiproliferation efficacy and tubulin polymerization inhibitory activity. Inferring comparable antitubulin effect with the positive control Colchicine, A18 indicated obviously lower cyto-toxicity. The cell scratch test showed that A18 could block the cell migration, while the confocal imaging depicted that A18 could induce the mitotic catastrophe via a Colchicine-like approach. The docking simulation visualized the probable binding pattern of A18. With the information in this work, some new hints on modification might be involved in further tubulin-related investigations.

Rational design, synthesis and biological evaluation of novel 2-(substituted amino)-[1,2,4]triazolo[1,5-a]pyrimidines as novel tubulin polymerization inhibitors

Following our previously reported compound 3, we designed and synthesized a series of new 2-(substituted amino)- [1,2,4]triazolo[1,5-a]pyrimidines as potential tubulin polymerization inhibitors. Among them, analogue 4k, having a 3-hydroxy-4-methoxyphenylamino group, was observed to display excellent antiproliferative activity toward HeLa, HCT116, A549, and T47D with the IC50 values of 0.31, 1.28, 3.99 and 10.32 μM, respectively, which were approximately 32, 48, 4, and 5-fold improvement compared with 3. Importantly, 4k possessed significant selectivity in inhibiting cancer cell lines over the normal HEK293 cells. Moreover, futher mechanism analysis demonstrated that 4k caused G2/M arrest, induced cells apoptosis in HeLa cells, and manifested significant tubulin polymerization inhibitory activity with the IC50 value of 4.9 μM, which is comparable to CA-4 (IC50 = 4.2 μM). The observations performed in this study reveal that 2-arylamino- [1,2,4]triazolo[1,5-a]pyrimidines represent a novel class of tubulin polymerization inhibitors with potent antiproliferative efficacy.

Discovery of polymethoxyphenyl-pyridines bearing amino side chains as tubulin colchicine-binding site inhibitors

Nineteen TH03 analogues were designed and synthesized as tubulin colchicine-binding site inhibitors with potent antiproliferative activities. Among these compounds, 3,5-dimethoxyphenylpyridines 8j bearing a 4-methoxybenzyl aniline side-chain displayed the best antiproliferative activities against glioma (U87MG and U251). In addition, the trimethoxyphenylpyridine 8o bearing a 4-methyl-N-methyl aniline side-chain showed the best antiproliferative activities against colon carcinoma and lung cancer with the lowest IC50 value (0.09 µM < IC50 < 0.86 µM). Compared with CA-4, Compounds 8j and 8o displayed lower cytotoxicities toward normal cells but higher antiproliferative activities against RKO (IC50 = 0.15 µM and 0.09 µM respectively), NCI-H1299 (IC50 = 0.73 µM and 0.14 µM respectively), and A549 cells (IC50 = 0.86 µM and 0.37 µM respectively). Further investigations revealed that 8o shows higher tubulin polymerization inhibitory activity (IC50 = 3.1 ± 0.5 µM) than colchicine (IC50 = 8.6 ± 0.2 µM), and induced cell cycle arrest at the G2/M phase and cellular apoptosis through disrupting the microtubule network.

Synthesis and screening of novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines as antiproliferative and tubulin polymerization inhibitors

Colchicine binding site represent a crucial target for the anticancer drug development especially in view of emerging drug resistance from the currently available chemotherapeutics. A total of 16 novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines were synthesized and screened for antiproliferative and tubulin polymerization inhibition potential. The synthesized compounds were evaluated against MCF-7, HeLa and HT-29 cancer cell lines and normal cell line HEK-293 T. In the series, 2‑aryl group with 4‑bromophenyl substitution displayed IC50 values of 6.37 µM, 17.43 µM, 6.76 µM and 4‑chlorophenyl substitution displayed IC50 values of 2.16 µM, 8.53 µM, 10.42 µM against MCF-7, HELA and HT29 cancer cell lines, respectively. In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, both the lead compounds were found to induce mitochondria mediated apoptosis and lead molecule with 4‑chlorophenyl substitution displayed significant tubulin polymerization inhibition activity. In the computation studies, lead molecule displayed significant binding affinites in the colchicine domain and showed good thermodynamic stability during 100 ns MD simulation studies. 4-N-Heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines showed appreciable drug like characteristics and can be developed as potent anticancer agents.

Synthesis of indole-tetrazole coupled aromatic amides; In vitro anticancer activity, in vitro tubulin polymerization inhibition assay and in silico studies

Herein, we described the synthesis of indole-tetrazole coupled aromatic amides (6a-o) and evaluated their in vitro anticancer activity. Some of the compounds namely N-(4-methoxyphenyl)-2-(5-(1-methyl-1H-indol-3-yl)-2H-tetrazol-2-yl)acetamide (6a), N-(3,5-dimethoxyphenyl)-2-(5-(1-methyl-1H-indol-3-yl)-2H-tetrazol-2-yl)acetamide (6b) and N-(4-cyanophenyl)-2-(5-(1-methyl-1H-indol-3-yl)-2H-tetrazol-2-yl)acetamide (6f) were found to be more active than the standard etoposide against three human cancer cell lines such as MCF-7 (breast), A549 (lung) and SKOV3 (ovarian) with IC50 values in the range of 3.5–8.7 µM. The in vitro tubulin polymerization inhibitory activity reveals that the compounds 6a and 6f were having double potency in inhibiton of tubulin polymerization than the standard combretastatin A-4 (CA-4). The molecular docking studies of three active compounds 6a, 6b and 6f on α,β−tubulin were also conducted and found that they have good binding interactions with the target protein. Finally, the in silico ADMET of potent compounds 6a, 6b and 6f were also studied, where all the compounds following Lipinski rule, Ghose rule, Veber rule, Egan rule and Muegge rule without any deviation.