Design and synthesis of some novel pyridothienopyrimidine derivatives and their biological evaluation as antimicrobial and anticancer agents targeting EGFR enzyme

A new series of pyridothienopyrimidine derivatives was designed and evaluated as antimicrobial and anticancer agents. The target compounds were synthesized starting with 3-aminothieno[2,3-b]pyridine-2-carboxamide derivative 1 which underwent cyclocondensation reaction with aromatic aldehydes to give the key intermediates 2a,b. By further treatment of 2a,b with various reagents, the target 2,4-disubstituted-pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidines 3a,b–11a,b were obtained. To evaluate the antimicrobial activity of the new compounds, they were tested against five bacterial and five fungal strains. Compounds 6c, 8b, 9a and 9b revealed the most significant antimicrobial activity against the tested microorganisms with MIC values range (4–16 μg/mL). Also, compounds 2a,b–11a,b were screened for their in vitro cytotoxic activity against HepG-2 and MCF-7 cancer cell lines compared with doxorubicin and cisplatin as references drugs. Moreover, compounds (2b, 4a, 6a, 7b, 7c and 9a) which exhibited the most potent anticancer activity, were further subjected to EGFR^WT enzyme inhibition assay utilizing erlotinib as a standard drug. The compounds 6a, 7b, 7c and 9a which showed the most promising suppression effects were also evaluated as inhibitors against the mutant forms EGFR^L858R and EGFR^T790M. The 4-aminopyrazolone analogue 9a showed superior anticancer activity against both HepG-2 and MCF-7 cell lines (IC50 = 1.27, 10.80 μM, respectively) and more potent enzymatic inhibition activity against EGFR^WT and its mutant forms EGFR^L858R and EGFR^T790M than that obtained by erlotinib (IC₅₀ = 0.021, 0.053, 0.081 µM, respectively, IC_50erlotinib; 0.027, 0.069, 0.550 µM, respectively). Finally, the molecular docking study showed good binding patterns of the most active compounds with the prospective target EGFR^WT.     

Synthesis,pharmacological evaluation,and molecular modeling studies of novel isatin hybrids as potential anticancer agents

A novel series of isatin hybrids 5a-g was designed, synthesized, and characterized spectroscopically. The synthesized compounds were evaluated for their cytotoxic activity against the human breast cancer cell line (MCF-7) by in vitro MTT assay. Amongst the tested compounds, 5e compound bearing benzyl moiety at N₄ piperazine was found to be the most active with the promising IC₅₀ (12.47 µM). Moreover, the active compounds 5e and 5g were subjected to antitumor evaluation (in vivo) against Dalton’s ascitic lymphoma (DAL) cell line and the results suggested that the best active compound 5e can normalize the blood picture in comparison to the standard drug. An in silico molecular docking study using the crystal structure of Hsp90 protein described the role of significant protein–ligand interactions and revealed more insights into the binding mode. The drug-likeliness of the compounds was predicted based on Lipinski's rule of five and pharmacokinetic ADME parameters. Hence, the synthesized isatin hybrids could be novel starting point anticancer lead compounds demonstrating drug-like properties which can be explored further for anticancer drug discovery.     

[Et3NH][HSO4]-mediated efficient synthesis of novel xanthene derivatives and their biological evaluation

A series of novel 2-chloro quinoline incorporated xanthene derivatives were synthesized by using various 2-chloro 3-formyl quinoline, dimedone and triethylammonium hydrogen sulfate [Et₃NH][HSO₄] as a catalyst as well solvent to give good to excellent yields. All the xanthene compounds were investigated for their in vitro antimycobacterial activity against M. tuberculosis H37Ra (MTB) and M. bovis BCG strains. Among the synthesized compounds 3a, 3c, 3d, 3e, 3g, 3h and 3k were highly potent against both the strains. Most of the active compounds were non-cytotoxic against THP-1, HCT-116, A549 and MCF-7 cell lines. Most active compounds were having higher selectively index which suggested that these compound were highly potent.     

Synthesis of functionalized aminopyrazole and pyrazolopyrimidine derivatives: Molecular modeling and docking as anticancer agents

Three new functionalized 4-aminopyrazole derivatives were synthesized and cyclized with phenyl isothiocyanate to yield the corresponding three pyrazolo[4,3-d]pyrimidine analogues. The DFT quantum chemical calculations were utilized in the determination of the frontier molecular orbital energies and Fukui’s indices. The data showed that they have a low HOMO-LUMO energy gap, ranging from 1.16 to 2.35 eV for 5 and 6, respectively. The newly created analogues' cytotoxic qualities were evaluated in comparison to the reference 5-florouracil (5-Fu) using an in vitro MTT cytotoxicity screening investigation toward four different cell lines, including HCT-116, HepG2, MCF-7, and WI38. The results showed variable potency against human cell lines, with MCF-7 and HepG-2 showing cytotoxic selectivity. The most potent agent against MCF-7 and HCT-116 human cancer cells were found to be aminopyrazole and pyrazolopyrimidine derivatives 4–9. The structure–activity relationships (SAR) for the synthesized compounds were discussed. The examined compounds had superior cytotoxic properties; the most potent derivative 7, had an IC₅₀ ranged from 11.51 ± 0.35 to 21.25 ± 0.37 µM. Meanwhile, quantum chemical computation used independent variables E_H, E_L, ΔE_H-L, χ and η were applied to determine the best way to describe activity. As a result, an increase in the HOMO-LUMO gap and hardness will result in an increase in the anticancer activity. While the E_H, E_L, and showed negative coefficients, increasing them will decrease the anticancer activity. Furthermore, 5IVE protein's crystal structure for KDM5A was docked with the newly created aminopyrazole and pyrazolopyrimidine derivatives to afford the theoretical prediction on the KDM5A enzyme.     

Design,synthesis, antimicrobial evaluations and in silico studies of novel pyrazol-5(4H)-one and 1H-pyrazol-5-ol derivatives

A new series of 1,4-disubstituted 3-methylpyrazol-5(4H)-one derivatives were synthesized by reacting various substituted aromatic aldehydes with 3-methylpyrazol-5(4H)-one derivatives through Knoevenagel condensation by conventional as well as by exposure to microwave irradiations. After that newly synthesized compounds of 1,4-disubstituted 3-methyl-1H-pyrazol-5-ol were prepared from these derivatives by reduction reaction of sodium borohydride at 0–5 °C. Sixty-four heterocyclic compounds containing a pyrazole moiety were synthesized with good to excellent yields (51 to 91%). Compounds (3d, 3m, 4a, 4b, 4d, and 4g) showed potent antibacterial activity against MSSA (Methicillin-susceptible strains of Staphylococcus aureus) and MRSA (Methicillin-resistant strains of Staphylococcus aureus) with MIC (the minimum inhibitory concentration) ranging between 4 and 16 µg/mL as compared to ciprofloxacin (MIC = 8–16 µg/mL). Compounds (4a, 4h, 4i, and 4l) showed potent antifungal activity against Aspergillus niger with MIC ranging between 16 and 32 µg/mL as compared to fluconazole (MIC = 128 µg/mL). In particular, compound 4a exhibited the strongest activity among the synthesized compounds in both bacterial and fungal strains with MIC ranging between 4 and 16 µg/mL. Furthermore, the nine most active compounds showed a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile in comparison to ciprofloxacin and fluconazole as reference drugs. Molecular docking predicted that DHFR (dihydrofolate reductase) protein from Staphylococcus aureus and NMT (N-myristoyl transferase) protein from Candida albicans are the most suitable targets for the antimicrobial activities of these potent compounds.     

Synthesis and biological applications of some novel 8-Hydroxyquinoline urea and thiourea derivatives

A number of novel urea and thiourea derivatives of 8-hydroxyquinoline have been designed, synthesized and evaluated for their anticancer activities. The structures of the new compounds were established by spectroscopic techniques, ¹H NMR, ¹³C NMR, and mass spectrometry. The in vitro cytotoxicity against MCF7, and MDA-MB-231 cell lines were assessed by MTT assay. Six of the 11 compounds synthesized namely 5b, 5c, 5f, and 6b-d exhibited cytotoxicity with IC₅₀ values ranged between 0.5 and 42.4 µM. Apoptotic features of cells treated with 5b compound were observed via florescent microscopy using DAPI and ethidium bromide/acridine orange staining against MCF-7 cells. Molecular docking of these molecules against 16 potential breast cancer protein revealed that these compounds could interact with the active site of poly (ADP-ribose) polymerase-1 (PARP1), B-cell lymphoma-extra large (Bcl-xL) and PARP5A (Tankyrase 1) by forming hydrogen bonds, π-π interactions and hydrophobic interactions. The docked poses of these molecules were observed to be similar in the active site of each of these targets.     

Design,synthesis and biological evaluation of isoxazole-naphthalene derivatives as anti-tubulin agents

In this study, a novel series of isoxazole-naphthalene derivatives as tubulin polymerization inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against human breast cancer cell line MCF-7. Most of the synthesized compounds exhibited moderate to potent antiproliferative activity (IC₅₀ < 10.0 μM), as compared to cisplatin (15.24 ± 1.27 μM). Among them, compound 5j containing 4-ethoxy substitution at phenyl ring was found to be the most active compound with IC₅₀ value of 1.23 ± 0.16 μM. Mechanistic studies revealed that compound 5j arrested cell cycle at G2/M phase and induces apoptosis. Furthermore, in vitro tubulin polymerization assay showed that compound 5j displayed better inhibition activity on tubulin polymerization (IC₅₀ = 3.4 μM) than colchicine (IC₅₀ = 7.5 μM). Molecular docking study also revealed that compound 5j binds to the colchicine binding site of tubulin.     

A novel class of 1,4-disubstituted 1,2,3-triazoles: Regioselective synthesis,antimicrobial activity and molecular docking studies

A Novel class of 1,4-disubstituted 1,2,3-triazoles have been synthesized in good to excellent yields via Cu(I) accelerated azide-alkyne click chemistry reaction strategy. The newly synthesized compounds were assessed for their in vitro antimicrobial activity against five Gram-positive, seven Gram-negative bacteria and three fungi. Most of the synthesized compounds displayed significant activity against the tested Gram-positive and Gram-negative bacteria. Molecular docking study revealed that all docked compounds are bound efficiently with the active site of Topoisomerase IV (4EMV) receptor with the observed the free energy of binding from −7.79 to −9.44 kcal/mol. Interestingly, compound 13a forms four hydrogen bonds and displayed high binding energy (−9.44 kcal/mol) with the Topoisomerase IV (4EMV) receptor which correlated with their in vitro antimicrobial assays.     

Optimization of pyrazolo[1,5-a]pyrimidine based compounds with pyridine scaffold: Synthesis,biological evaluation and molecular modeling study

BackgroundPyrazolopyrimidine heterocycle and its isosteres represent the main scaffold for many pharmacologically active drugs including anti-inflammatory agents. The COX-2 inhibitors are the principal gate for the design of new safe and potent anti-inflammatory agents.MethodsNovel derivatives of pyrazolo[1,5-a] pyrimidines were synthesized and screened in vivo and in vitro for their anti-inflammatory potential.ResultsWithin the constructed compounds, compound 11 was the most active compound on IL-6 and TNF-α (percentage inhibition = 80 and 89%, respectively). In addition, compound 12 displayed the most inhibitory effect towards COX-2 (IC₅₀ = 1.11 µM), whereas compound 11 recorded the highest COX-2 selectivity (S.I = 8.97). The target derivatives 11–14 displayed good edema inhibitory potential (46–68%) and compound 11 was the most potent candidate (ED₅₀ = 35 mg/kg). Additionally, the most potent sPLA2-V inhibitors were compounds 11 and 13 (IC₅₀ = 1 and 1.7 µM respectively). Regarding activity towards 15-LOX, derivative 12 was the most active compound with IC₅₀ = 5.6 µM revealing higher inhibitory activity than nor-dihydroguaiaretic acid (IC₅₀ = 8.5 µM). To confirm the anti-inflammatory potential of the target derivatives, molecular modeling was performed inside COX-2 and 15-LOX active sites.ConclusionDisplay discoveries increment the plausibility that these pyrazolo[1,5-a]pyrimidines might act as a beginning point for the improvement of anti-inflammatory agents.     

Design,cytotoxic effects on breast cancer cell line (MDA-MB 231), and molecular docking of some maleimide-benzenesulfonamide derivatives

A group of novel maleimide-benzenesulfonamide derivatives 3a-d was designed and synthesized for their evaluation as a potential anti-breast cancer agent. The structures of these derivatives were confirmed by their ¹H, ¹³C NMR, Mass, FT-IR spectral data, and melting points. The cytotoxic activity (in vitro) of the selected molecules against MDA-MB231 ​cell line was evaluated by MTT method. Among them, compounds 3a and 3d exhibited a significant cytotoxicity with the IC₅₀ value of 1.61 and 1.26 ​μM, respectively, whereas compounds 3b and 3c showed a moderate cytotoxicity with IC₅₀ values of 0.45 and 1.12 ​μM, respectively against MDA-MB231 ​cells. Docking modeling of the synthesized compounds 3a-d into binding sites of human aromatase protein (PDB ID: 4GL7) was performed to investigate if these derivatives possess analogous binding mode to breast cancer proteins. Docking results showed these compounds have efficient interactions such as hydrogen bonding, Van der Waals interactions, and hydrophobic interactions with the active site residues of the aromatase protein (PDB ID: 4GL7). The low binding energies and a number of hydrogen bonding indicated that the maleimide-benzenesulfonamide derivatives might be considered as a promising anti-breast cancer agent with further developments in drug discovery.     

Design,synthesis, docking and mechanistic studies of new thiazolyl/thiazolidinylpyrimidine-2,4-dione antiproliferative agents

In this article, we display on the synthesis and biological evaluation of a new series of thiazolylpyrimidine 3a-l and thiazolidinylpyrimidine derivatives 5a-e. The structures of the new compounds were confirmed by using different spectral techniques including NMR, IR, mass spectroscopy in addition to elemental analyses. The cell viability of the new compounds was assessed against normal human mammary gland epithelial (MCF-10A) cell line. Data revealed that none of the compounds examined exhibited cytotoxic effects, and the cell viability for the compounds examined at 50 µM was greater than 87%. The antiproliferative activity of 3a-l and 5a-e was evaluated against four human cancer cell lines where the compounds showed promising activity. The most potent derivatives were compounds 3a, 3c, 3f, 3i, and 5b with GI₅₀ values ranging from 0.90 µM to 1.70 µM against the four cancer cell lines in comparison to doxorubicin (GI₅₀ = 1.10 µM). Compounds 3a, 3c and 3i showed potent antiproliferative activity with dual inhibitory action against EGFR and BRAF^V600E. Compounds 3a, 3c, and 3i demonstrated promising AutoDock scores towards EGFR and BRAF^V600E with values of ? 9.1 and ? 8.6, ?9.0 and ? 8.5, and ? 8.4 and ? 8.0 kcal/mol, respectively. The physicochemical and pharmacokinetic characteristics of 3a, 3c, and 3i were anticipated, demonstrating their oral bioavailability.     

Design,synthesis of new novel quinoxalin-2(1H)-one derivatives incorporating hydrazone,hydrazine, and pyrazole moieties as antimicrobial potential with in-silico ADME and molecular docking simulation

A series of 6-(morpholinosulfonyl)quinoxalin-2(1H)-one based hydrazone, hydrazine, and pyrazole moieties were designed, synthesized, and evaluated for their in vitro antimicrobial activity. All the synthesized quinoxaline derivatives were characterized by IR, NMR (¹H /¹³C), and EI MS. The results displayed good to moderate antimicrobial potential against six bacterial, and two fungal standard strains. Among the tested derivatives, six quinoxalin-2(1H)-one derivatives 4a, 7, 8a, 11b, 13, and 16 exhibited a significant antibacterial activity with MIC values (0.97–62.5 µg/mL), and MBC values (1.94–88.8 µg/mL) compared with Tetracycline (MICs = 15.62–62.5 µg/mL, and MBCs = 18.74–93.75 µg/mL), and Amphotericin B (MICs = 12.49–88.8 µg/mL, and MFC = 34.62–65.62 µg/mL). In addition, according to CLSI standards, the most active quinoxalin-2(1H)-one derivatives demonstrated bactericidal and fungicidal behavior. Moreover, the most active quinoxaline derivatives showed a considerable antibacterial activity with bactericidal potential against multi-drug resistance bacteria (MDRB) strains with MIC values ranged between (1.95–15.62 µg/mL), and MBC values (3.31–31.25 µg/mL) near to standard Norfloxacin (MIC = 0.78–3.13 µg/mL, and MBC = 1.4–5.32 µg/mL. Further, in vitro S. aureus DNA gyrase inhibition activity were evaluated for the promising derivatives and displayed potency with IC₅₀ values (10.93 ± 1.81–26.18 ± 1.22 µM) compared with Ciprofloxacin (26.31 ± 1.64 µM). Interestingly, these derivatives revealed as good immunomodulatory agents by a percentage ranging between 82.8 ± 0.37 and 142.4 ± 0.98 %. Finally, some in silico ADME, toxicity prediction, and molecular docking simulation were performed and showed a promising safety profile with good binding mode.     

The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis,biological evaluation and in silico docking studies

An enhanced acetylcholinesterase (AChE) activity is a hallmark in early stages of Alzheimer's ailment that results in decreased acetylcholine (ACh) levels, which in turn leads to cholinergic dysfunction and neurodegeneration. Consequently, inhibition of both AChE and butyrylcholinesterase (BChE) is important to prolong ACh activity in synapses for the enhanced cholinergic neurotransmission. In this study, a series of new fluoroquinolone derivatives (7a-m) have synthesized and evaluated for AChE and BChE inhibitory activities. The screening results suggested that 7 g bearing ortho fluorophenyl was the most active inhibitor against both AChE and BChE, exhibiting IC₅₀ values of 0.70 ± 0.10 µM and 2.20 ± 0.10 µM, respectively. The structure–activity relationship (SAR) revealed that compounds containing electronegative functions (F, Cl, OMe, N and O) at the ortho position of the phenyl group exhibited higher activities as compared to their meta- and/or para substituted counterparts. Molecular docking studies of synthesized compounds 7a, 7g, 7j and 7l docked into the active site of AChE and 7a-f docked into the active site of BChE revealed that these compounds exhibited conventional H-bonding along with π-π interaction with the active residues of AChE through their electronegative functions and phenyl ring, respectively. All the synthesized compounds are characterized by spectroscopic methods including FT-IR, ¹H- and ¹³C NMR as well as elemental analysis. This is the first example of fluoroquinolone-based cholinesterase inhibitors.     

New synthetic quinaldine conjugates: Assessment of their anti-cholinesterase,anti-tyrosinase and cytotoxic activities,and molecular docking analysis

Despite all the progress made to enrich the existing bank of drugs used to treat and cure Alzheimer and cancer patients, there is still a need to research and develop new bioactive candidates with superior efficacy but minimal side effects. In this context, a new series of anti-butyrylcholinesterase (anti-BChE), anti-tyrosinase and cytotoxic succinimide linked quinaldine conjugates 3a-i was designed and synthesized starting from 8-hydroxyquinaldine. The condensation of quinoleine-hydrazide 2 with electrophilic species such as aromatic and nonaromatic anhydrides provided the new compounds 3a-i. These synthesized heterocycles were characterized by spectroscopic means (¹H NMR, ¹³C NMR and ESI-HRMS). Their anti-butyrylcholinesterase, anti-tyrosinase and cytotoxic (cervical cancer cell (HeLa) and lung cancer cell (A549)) activities have been evaluated in vitro. Compounds 3e and 3 g were found to be more anti-BChE than Galanthamine. Compounds 3d, 3e and 3 g exerted better anti-tyrosinase activity than kojic acid. Also, 3a, 3f and 3 g showed interesting cytotoxic potential towards HeLa cell lines. These results were supported by the molecular docking analysis (structure–activity relationship (SAR)) to estimate and discuss possible interactions between these derivatives and active sites of proteins butyrylcholinesterase (PDB: 4B0P), tyrosinase (PDB: 2Y9X) and cytotoxic (topoisomerase IIα enzyme (PDB: 5GWK)).     

Synthesis,antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl heterocycles: 1st Cancer Update

A series of 1-(N-methyl 2a–c and N-benzenesulphonyl-1H-indol-3-yl)-3-aryl-prop-2-ene-1-ones 3a–c were prepared and allowed to react with urea, thiourea or guanidine and gave the pyrimidine derivatives 4a–c to 9a–c. Base catalyzed reaction of 2a–c or 3a–c with ethyl acetoacetate gave cyclohexanone derivatives 10a–c and 11a–c, respectively. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 12a–c and 13a–c, respectively. On the other hand, condensation of 2c or 3c with some hydrazine derivatives namely, hydrazine hydrate, acetyl hydrazine, phenyl hydrazine and benzyl hydrazine hydrochloride gave pyrazole derivatives 14a,b-17a,b, respectively. Moreover, reaction of 2c or 3c with hydroxyl amine hydrochloride gave isoxazole derivatives 18a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that, compounds 14a, 14b, 15a and 15b were found to be the most active ones of all the tested compounds toward Salmonella typhimurium (ATCC 14,028) compared to the reference drug chloramphenicol. Eighteen new compounds namely, pyrimidin-2(1H)-ones 4a–c and 5a–c, pyrimidin-2(1H)-thiones 6a–c and 7a–c and pyrimidin-2-amines 8a–c and 9a–c were tested for their in vitro cytotoxicity against human liver carcinoma (HEPG2), human breast cancer (MCF7) and human colon cancer (HCT-116) cell lines and showed that, compounds 4c, 5c, 6c, 8c and 9c were found to be the highly active compounds compared to the reference drug doxorubicin.     

Synthesis and biological evaluation of new 9-aminoacridine-4-carboxamide derivatives as anticancer agents: 1st Cancer Update

The design of molecules that recognize the specific sequence of the DNA double helix or those that can stabilize DNA topoisomerase cleavable complex to stop the progression of DNA process, may be very useful in cancer chemotherapy. In the field of antituor DNA-intercalating agents, 9-aminoacridine-4-carboxamide derivatives play an important role due to their anti-proliferative properties. In the present study, 9-aminoacridine-4-carboxamide derivatives were designed, synthesized, characterized and evaluated against lung cancer (A-549) cell line and cervical cancer (HeLa) cell line in vitro by MTT assay. Compounds 5a, 5b and 5e were selected for anticancer evaluation against the lung cancer cell line and cervical cancer cell line. Compound 5b showed the maximum activity against the cervical cancer (HeLa) cell line with CTC₅₀ (47.50 μg/ml) and compound 5e showed the maximum activity against the lung cancer (A-549) cell line with CTC₅₀ (100 μg/ml) among the tested compounds. The present study opens new vista for DNA intercalating anticancer compounds and their further in vivo investigation.     

Synthesis and anti-tumor activity evaluation of novel podophyllotoxin derivatives

In order to investigate the effects on the cytotoxicity of indole-3-oxalylamino podophyllotoxin analogs, seven novel podophyllotoxin derivatives were synthesized.The compounds were tested against Hela, K562 or K562/A02 cancer cells in vitro,four of which showed significant cytotoxicity.Among them 9a,9b and 9c were superior to the positive control VP-16.     

Design,synthesis and biological evaluation of novel 2-phenyl-4,5,6,7-tetrahydro-1H-​indole derivatives as potential anticancer agents and tubulin polymerization inhibitors

A new series of 2-phenyl-4,5,6,7-tetrahydro-1H-?indole derivatives as tubulin polymerization inhibitors were synthesized and evaluated for the anti-proliferative activities. All newly prepared compounds were tested for their antiproliferative activity in vitro on the human breast cancer cell line (MCF-7) and human lung adenocarcinoma cell line (A549). Among them, compound 7b with a 4-methoxyl substituent at the phenylhydrazone moiety exhibited the most potent anticancer activity against MCF-7 and A549 with IC₅₀ values of 1.77 ± 0.37 and 3.75 ± 0.11 μM, respectively. Interestingly, 7b displayed significant selectivity in inhibiting cancer cells over LO2 (normal human liver cells). Further mechanism studies revealed that 7b significantly arrested cell cycle at G2/M phase and induced apoptosis in a dose-dependent manner. Additionally, 7b effectively inhibited tubulin polymerization with an inhibitory manner similar to that of colchicine. Furthermore, molecular docking study suggested that 7b had high binding affinities for the colchicine binding pocket of tubulin. Hence, this study demonstrates for the first time that tetrahydroindole can be used as a functional group for the design and development of new tubulin polymerization inhibitors.     

Design,synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects

A series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4-disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized compounds was investigated against four human cancer cell lines using an MTT assay. Compounds 5d, 5e, and 5f revealed the most potent antiproliferative activity with GI₅₀ values ranging from 0.70 µM to 1.20 µM, compared to doxorubicin GI₅₀ value = 1.10 µM. Compounds 5d, 5e, and 5f were further investigated for their inhibitory activities against CDK2 and EGFR as potential targets for their molecular mechanism. Compounds 5e and 5f have showed potent inhibitory activity to CDK2 enzyme with IC₅₀ values of 18 and 14 nM, which is more potent than the reference dinaciclib (IC₅₀ = 20 nM). Moreover, compounds 5e and 5f were the most potent EGFR inhibitors, with IC₅₀ values of 93 and 87 nM, respectively, compared to the reference erlotinib (IC₅₀ = 70 nM). In addition, the most potent derivatives were tested for their apoptotic activity against caspases 3, 8, and 9, and the results showed that compounds 5d, 5e, and 5f revealed a greater increase in active caspases 3,8 and 9 than doxorubicin. Also, compounds 5d, 5e, and 5f elevated cytochrome C levels in the MCF-7 human breast cancer cell line by about 15.5, 15.8, and 16.5 times, respectively. Finally, a molecular docking study was performed to investigate the binding sites of these compounds within the active sites of CDK2 and EGFR targets, and the results confirmed that the most potent CDK2 and EGFR inhibitor 5h also have showed the highest docking score.     

Efficient synthesis of new oxindol-based heterocyclic entities via indolin-2-one derivatives

New series of oxindol-based heterocyclic entities (2–11) have been designed and synthesized using indolin-2-one derivatives as key materials (1a–d). The chemical structures of the new synthesized compounds were characterized by FTIR, ¹HNMR, ¹³CNMR, MS spectroscopy and elemental analyses. Three of the newly synthesized compounds were tested for anticancer activity in the National Cancer Institute (NCI) against human panel breast cancer cell line MCF7, from the in vitro assays compound 6c presented promising anti-cancer activity using Doxorubicin as a reference. Compound 6c could be a lead compound for discovery of new anticancer agent.