Synthesis,biological evaluation and molecular modeling of 1,3,4-thiadiazol-2-amide derivatives as novel antitubulin agents

A series of 1,3,4-thiadiazol-2-amide derivatives (6a–w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC₅₀ values of 0.03 μM, 0.06 μM and 0.05 μM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC₅₀ = 1.73 μM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.     

New antiproliferative 7-(4-(N-substituted carbamoylmethyl)piperazin-1-yl) derivatives of ciprofloxacin induce cell cycle arrest at G2/M phase

New N-4-piperazinyl derivatives of ciprofloxacin 2a–g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC₅₀ = 14.8, 24.8, 23.6 and 20.7 μM, respectively) compared to the parent ciprofloxacin (IC₅₀ >100 μM) and doxorubicin as a positive control (IC₅₀ = 1 μM). The flow cytometric analysis for 2b showed dose dependent G₂/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G₂/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G₂/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer.     

5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potential anticancer agents with anti-inflammatory properties

A series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (3a–z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI₅₀ = 850 nM), against leukemia SR cancer cells (GI₅₀ = 1.45 μM), and OVCAR-3 (GI₅₀ = 1.26 μM) ovarian cancer cell lines. The structurally related compound 3s had a GI₅₀ value of 1.77 μM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI₅₀ values of 1.30 and 1.91 μM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI₅₀ values of 1.09 μM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy.     

A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole–thiochroman hybrids and evaluation of their antimycobacterial,anticancer and AchE inhibitory activities

A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole–thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC₅₀ 1.07 μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC₅₀ <1.56 μM) and 6l (IC₅₀ = 2.87 μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC₅₀ values of 1.10 and 1.16 μmol/L respectively.     

New antiprotozoal agents: Synthesis and biological evaluation of different 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives

In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives (5–14) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC₅₀ values (0.14–1.26 μM) lower than the standard drug metronidazole (IC₅₀ 1.80 μM). All nine compounds exhibited antimalarial activity (IC₅₀ range: 1.42–19.62 μM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC₅₀ range: 14.67–81.24 μM) than quinine (IC₅₀: 275.6 ± 16.46 μM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae.     

Synthesis of (benzimidazol-2-yl)aniline derivatives as glycogen phosphorylase inhibitors

A series of (benzimidazol-2-yl)-aniline (1) derivatives has been synthesized and evaluated as glycogen phosphorylase (GP) inhibitors. Kinetics studies revealed that compounds displaying a lateral heterocyclic residue with several heteroatoms (series 3 and 5) exhibited modest inhibitory properties with IC₅₀ values in the 400–600 μM range. Arylsulfonyl derivatives 7 (Ar: phenyl) and 9 (Ar: o-nitrophenyl) of 1 exhibited the highest activity (series 2) among the studied compounds (IC₅₀ 324 μM and 357 μM, respectively) with stronger effect than the p-tolyl analogue 8.     

Synthesis and biological evaluation of novel C6-amino substituted 4-azasteroidal purine nucleoside analogues

Novel C6-amino substituted purine nucleoside analogues (2–12) bearing a modified pyranose-like D ring of the 4-azasteroid moiety were efficiently synthesized through nucleophilic substitution at C6 position of the steroidal nucleoside precursors (1a, b) with versatile amines. All the synthesized new compounds were evaluated for their anticancer activity in vitro against Hela, PC-3 and MCF-7 cell lines. Among them, compounds 4b, 7b and 9b exhibited significant cytotoxicity with the IC₅₀ values of 2.99 μM (PC-3), 2.84 μM, (PC-3) and 2.69 μM (Hela), respectively.     

Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V3 (V1b) receptor antagonists

The discovery, synthesis, and preliminary structure–activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS? technology, had good activity in a V3 binding assay (IC₅₀ = 0.20 μM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC₅₀ = 0.31 μM) and 24 (IC₅₀ = 0.12 μM) with improved drug-like characteristics.     

Design and synthesis of novel 2-methyl-4,5-substitutedbenzo[f]-3,3a,4,5-tetrahydro-pyrazolo[1,5-d][1,4]oxazepin-8(7H)-one derivatives as telomerase inhibitors

Eight novel 4,5-tetrahydropyrazolo[1,5-d][1,4]oxazepine derivatives have been synthesized and purified to be screened for anticancer activity. By a modified TRAP assay, some titled compounds were tested against telomerase, and compound 4a showed the most potent inhibitory activity with IC₅₀ value at 0.78 ± 0.22 μM. Western blot assays showed that compounds 4a and 4b could inhibit expression of Cyclin D1, TERT, phospho-AKT and PI3K/AKT pathway.     

Design,synthesis and biological evaluation of heterocyclic azoles derivatives containing pyrazine moiety as potential telomerase inhibitors

Three series of novel heterocyclic azoles derivatives containing pyrazine (5a–5k, 8a–8k and 11a–11k) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential telomerase inhibitors. Among the oxadiazole derivatives, compound 5c showed the most potent biological activity against SW1116 cancer cell line (IC₅₀ = 2.46 μM against SW1116 and IC₅₀ = 3.55 μM for telomerase). Compound 8h performed the best in the thiadiazole derivatives (IC₅₀ = 0.78 μM against HEPG2 and IC₅₀ = 1.24 μM for telomerase), which was comparable to the positive control. While compound 11f showed the most potent biological activity (IC₅₀ = 4.12 μM against SW1116 and IC₅₀ = 15.03 μM for telomerase) among the triazole derivatives. Docking simulation by positioning compounds 5c, 8h and 11f into the telomerase structure active site was performed to explore the possible binding model. The results of apoptosis demonstrated that compound 8h possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 8h with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell. Therefore, the introduction of oxadiazole, thiadiazole and triazole structures reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity.     

Synthesis and molecular docking studies of novel 2-chloro-pyridine derivatives containing flavone moieties as potential antitumor agents

A series of novel 2-chloro-pyridine derivatives containing flavone, chrome or dihydropyrazole moieties as potential telomerase inhibitors were synthesized. The bioassay tests showed that compounds 6e and 6f exhibited some effect against gastric cancer cell SGC-7901 with IC₅₀ values of 22.28 ± 6.26 and 18.45 ± 2.79 μg/mL, respectively. All title compounds were assayed for telomerase inhibition by a modified TRAP assay, the results showed that compound 6e can strongly inhibit telomerase with IC₅₀ value of 0.8 ± 0.07 μM. Docking simulation was performed to position compound 6e into the active site of telomerase (3DU6) to determine the probable binding model.     

New phenolic glycosides with cyclooxygenase inhibition from the roots of Tecoma mollis

Three new phenolic glycosides (1–3) together with nine known ones were isolated from the roots of Tecoma mollis using DPPH radical scavenging bioassay-guided chromatographic separation. The structures of the new compounds were established using extensive spectroscopic data and HR-MS. The antioxidant, COX-2 inhibition, and cytotoxic activities were evaluated for the isolated compounds. Compound 4 displayed the strongest radical scavenging activity relative to ascorbic acid with IC₅₀ 8.7 μM. Compounds 5, 6, and 10 showed promising COX-2 inhibitory action, IC₅₀ values of 11.3 μM, 9.4 μM, and 13.4 μM, respectively. All compounds exhibited weak cytotoxic activity against Hela and A549 cancer cell lines.     

Synthesis,biological evaluation, 3D-QSAR studies of novel aryl-2H-pyrazole derivatives as telomerase inhibitors

A series of novel aryl-2H-pyrazole derivatives bearing 1,4-benzodioxan or 1,3-benzodioxole moiety were designed as potential telomerase inhibitors to enhance the ability of aryl-2H-pyrazole derivatives to inhibit telomerase, a target of anticancer. The telomerase inhibition tests showed that compound 16A displayed the most potent inhibitory activity with IC₅₀ value of 0.9 μM for telomerase. The antiproliferative tests showed that compound 16A exhibited high activity against human gastric cancer cell SGC-7901 and human melanoma cell B16-F10 with IC₅₀ values of 18.07 and 5.34 μM, respectively. Docking simulation showed that compound 16A could bind well with the telomerase active site and act as telomerase inhibitor. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent telomerase inhibitory activity.     

Synthesis and CYP24A1 inhibitory activity of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides

A series of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides were prepared, using an efficient three- to five-step synthesis, and evaluated for their inhibitory activity against human cytochrome P450C24A1 (CYP24A1) hydroxylase. Inhibition ranged from IC₅₀ 0.3–72 μM compared with the standard ketoconazole IC₅₀ 0.52 μM, with the styryl derivative (11c) displaying enhanced activity (IC₅₀ = 0.3 μM) compared with the standard, providing a useful preliminary lead for drug development.     

New coumestan and coumaronochromone derivatives from Dalbergia boehmii Taub. (Fabaceae)

Chemical investigation of leaves and heartwood of Dalbergia boehmii resulted in the isolation of two new phenolic compounds, designated dalbergestan (1) and dalbergichromone (2), along with eleven known compounds, carpachromene (3), proanthocyanidin A-2 (4); piceatannol (5); biochanin A (6); macckiain (7); homopterocarpin (8); angolensin (9); medicarpin (10); 2′,7-dihydroxy-4′,5′-dimethoxyisoflavone (11); 2′-methoxyformononetin (12); and genistein (13). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses including, IR, UV, 1D and 2D – NMR as well as HRMS data. Some of the isolated compounds were evaluated for their in vitro insulin secretion activity on isolated mice islets, leishmanicidal activity against L. major (DESTO) promastigotes and in vitro cytotoxicity on MCF-7 cell lines. All tested compounds were inactive on glucose-stimulated insulin secretion at stimulatory glucose (20.0 mM) from MIN6 cells. Compounds 3 (IC₅₀, 70.0 μg/ml), 6 (IC₅₀, 60.3 μg/ml), 7 (IC₅₀, 86.5 μg/ml) and 13 (IC₅₀, 62.6 μg/ml) exhibited low leishmanicidal activity while compound 12 (IC₅₀, 56.8 μg/ml) displayed a moderate activity. Compounds 3 and 5 were found to be active against MCF-7 at 50 μM with IC₅₀ value 33.2 ± 3.79 μg/ml and 42.64 ± 5.05 μg/ml respectively.     

Discovery of (E)-5-(benzylideneamino)-1H-benzo[d]imidazol-2(3H)-one derivatives as inhibitors for PTK6

A lead compound 1, which inhibits the catalytic activity of PTK6, was selected from a chemical library. Derivatives of compound 1 were synthesized and analyzed for inhibitory activity against PTK6 in vitro and at the cellular level. Selected compounds were analyzed for cytotoxicity in human foreskin fibroblasts using MTT assays and for selectivity towards PTK members in HEK 293 cells. Compounds 20 (in vitro IC₅₀ = 0.12 μM) and 21 (in vitro IC₅₀ = 0.52 μM) showed little cytotoxicity, excellent inhibition of PTK6 in vitro and at the cellular level, and selectivity for PTK6. Compounds 20 and 21 inhibited phosphorylation of specific PTK6 substrates in HEK293 cells. Thus, we have identified novel PTK6 inhibitors that may be used as treatments for PTK6-positive carcinomas, including breast cancer.     

Novel inhibitors of epidermal growth factor receptor: (4-(Arylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(1H-indol-2-yl)methanones and (1H-indol-2-yl)(4-(phenylamino)thieno[2,3-d]pyrimidin-6-yl)methanones

Several members of the quinazoline class of known tyrosine kinase inhibitors are approved anticancer agents, often showing selectivity for receptors of the HER/ErbB-family. Combining structural elements of this class with the bisindolylmethanone-structure led to a series of novel compounds. These compounds inhibited EGFR in the nanomolar range. Moreover, inhibition of EGFR autophosphorylation in intact A431 cells was shown, with IC₅₀ values ranging form 0.3–1 μM for compound 42, and 0.1–0.3 μM for 45. In a panel of 42 human tumor cell lines the sensitivity profile of the novel compounds was shown to be similar to that of the quinazoline class of tyrosine kinase inhibitors lapatinib and erlotinib (Tarceva®).     

Rational design,synthesis, anti-HIV-1 RT and antimicrobial activity of novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one derivatives

In the present study, fifteen novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one (6a-o) derivatives were designed as inhibitor of HIV-1 RT using ligand based drug design approach and in-silico evaluated for drug-likeness properties. Designed compounds were synthesized, characterized and in-vitro evaluated for RT inhibitory activity against wild HIV-1 RT strain. Among the tested compounds, four compounds (6a, 6b, 6j and 6o) exhibited significant inhibition of HIV-1 RT (IC₅₀ ⩽ 10 μg/ml). All synthesized compounds were also evaluated for anti-HIV-1 activity as well as cytotoxicity on T lymphocytes, in which compounds 6b and 6l exhibited significant anti-HIV activity (EC₅₀ values 4.72 and 5.45 μg/ml respectively) with good safety index.Four compounds (6a, 6b, 6j and 6o) found significantly active against HIV-1 RT in the in-vitro assay were in-silico evaluated against two mutant RT strains as well as one wild strain. Further, titled compounds were evaluated for in-vitro antibacterial (Escherichia coli, Pseudomonas putida, Staphylococcus aureus and Bacillus cereus) and antifungal (Candida albicans and Aspergillus niger) activities.     

Synthesis of novel 3,5-diaryl pyrazole derivatives using combinatorial chemistry as inhibitors of tyrosinase as well as potent anticancer,anti-inflammatory agents

In the present article, we have synthesized a combinatorial library of 3,5-diaryl pyrazole derivatives using 8-(2-(hydroxymethyl)-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-2-phenyl-4H-chromen-4-one (1) and hydrazine hydrate in absolute ethyl alcohol under the refluxed conditions. The structures of the compounds were established by IR, ¹H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their anticancer activity against five cell lines (breast cancer cell line, prostate cancer cell line, promyelocytic leukemia cell line, lung cancer cell line, colon cancer cell line) and anti-inflammatory activity against TNF-α and IL-6. Out of 15 compounds screened, 2a and 2d exhibited promising anticancer activity (61–73% at 10 μM concentration) against all selected cell lines and IL-6 inhibition (47% and 42% at 10 μM concentration) as in comparison to standard flavopiridol (72–87% inhibition at 0.5 μM) and dexamethasone (85% inhibition at 1 μM concentration), respectively. Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Out of 15, four 3,5-diaryl pyrazole derivatives exhibiting potent inhibitory activities against both the monophenolase and diphenolase actions of tyrosinase. The IC₅₀ values of compounds (2a, 2d, 2h and 2l) for monophenolase inhibition were determined to range between 1.5 and 30 μM. Compounds 2a, 2d, 2h and 2l also inhibited diphenolase significantly with IC₅₀ values of 29.4, 21.5, 2.84 and 19.6 μM, respectively. All four 3,5-diaryl pyrazole derivatives were active as tyrosinase inhibitors (2a, 2d, 2h and 2l), and belonging to competitive inhibitors. Interestingly, they all manifested simple reversible slow-binding inhibition against diphenolase.     

Synthesis and cytotoxic activity of nitric oxide-releasing isosteviol derivatives

Fifteen novel hybrids containing diterpene skeleton and nitric oxide (NO) donor were prepared from isosteviol. All the compounds were tested on preliminary cytotoxicity, and the results showed that six target compounds (8c, 10b, 14a, 14c, 18c, and 18d) exhibited anti-proliferation activity on HepG2 cells, with 8c (IC₅₀ = 4.24 μM) and 18d (IC₅₀ = 2.75 μM) superior to the positive control CDDO-Me (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-acid methyl ester, IC₅₀ = 4.99 μM); eleven target compounds (8a–c, 9a–c, 10a–b, 14a, 14c, 18d) exhibited anti-proliferation activities on B16F10 cells at different levels, among them, seven compounds were more potent than comptothecin (IC₅₀ = 2.78 μM) and CDDO-Me (IC₅₀ = 5.85 μM), particularly, 10b (IC₅₀ = 0.02 μM) presented the strongest effect, which was selected as a candidate for further study.