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,characterization, and anticancer activity of some metal complexes with a new Schiff base ligand

A new Schiff base ligand, 2-((E)-((4-(((E)-benzylidene)amino)phenyl)imino)methyl)-naphthalene-1-ol, was prepared by the reflux condensation of p-phenylenediamine with 2-hydroxy-1-naphthaldehyde and benzaldehyde. Metal complexes were prepared by reacting the ligand with metal salts: VCl₃, CrCl₃·6H₂O, MnCl₂·3H₂O, FeCl₃·6H₂O, CoCl₃·6H₂O, NiCl₂·6H₂O, CuCl₂·2H₂O, and ZnCl₂. The ligand and its metallic complexes were characterized by various techniques such as elemental analysis, AAS, NMR, IR, UV–Vis, TGA, DTA, XRD and TEM. The data confirmed that the ligand coordinated with the metal ions in a bidentate nature, bonding through its azomethine nitrogen atom and phenolic oxygen atom; this gave an octahedral geometry. The XRD patterns of the complexes indicated that they were of various structures: the Mn(II), Co(III), and Cu(II) complexes were triclinic, the ligand and Ni(II) complex were orthorhombic, the V(III) and Zn(II) complexes were hexagonal, the Cu(II) complex was monoclinic, and the Fe(II) complex was cubic. TEM analysis confirmed that the complexes were nanoscale in nature. The antibacterial and antifungal activities of the ligand and its complexes against Salmonella enterica serovar typhi and Candida albicans were investigated by the hole plate diffusion method. It was observed that the Co(II) and Zn(II) complexes had intermediate antibacterial activities, while the V(III) complex had the highest activity against C. albicans fungi. The in vitro anticancer activities of the ligand and its metal complexes were tested towards PC-3, SKOV3, and HeLa tumour cell lines, where they exhibited higher antitumour activities against these selected human cell lines than clinically used drugs such as cisplatin, estramustine, and etoposide.     

Synthesis and anticancer activity evaluation of 3-(4-oxo-2-thioxothiazolidin-5-yl)-1H-indole-carboxylic acids derivatives

Abstract

A mild and efficient method for the synthesis of 1-oxo-9H-thiopyrano[3,4-b]indole-3-carboxylic acids and dimerized 3-(4-carboxy-1H-3-indolyl)-2-propenoic acids via alkaline hydrolysis of 3-(rhodanin-5-yl)-1H-indole-2-carboxylic acids derivatives was elaborated. Anticancer activity screening in NCI60-cell lines assay allowed identification of 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic acid methyl ester 2a with significant antimitotic activity at micromolar and submicromolar concentrations.     

4-(1-Aryl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides: Synthesis,antimicrobial, anticancer evaluation and QSAR studies

A series of 4-(1-aryl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzenesulfonamide derivatives (1–20) was synthesized and evaluated for its in vitro antimicrobial and anticancer activities. Antimicrobial results indicated that compounds N-(4-(1-benzoyl-5-chloro-2-oxoindolin-3-ylideneamino) phenylsulfonyl)-4-isopropoxy benzamide (9) and N-(4-(5-chloro-1-(2-chlorobenzoyl)-2-oxoindolin-3-ylideneamino) phenylsulfonyl)-4-isopropoxybenzamide (19) were found to be the most effective ones. The anticancer results indicated that almost all the synthesized compounds were more active than the standard drug carboplatin but less active than the standard drug 5-fluorouracil (5-FU) against both the cell lines (HCT116 and RAW 264.7). 4-(1-Benzoyl-5-chloro-2-oxoindolin-3-ylideneamino)-N-(pyrimidin-2-yl) benzenesulfonamide (3) was found to be most potent and exhibited selectivity toward HCT 116. QSAR studies indicated that antimicrobial activity of isatin derivatives against different microbial strains was governed by lipophilic parameter, log P and topological parameters valance zero and third order molecular connectivity indices (⁰χ^v and ³χ^v).     

Synthesis,antimicrobial, anticancer,antiviral evaluation and QSAR studies of 4-(1-aryl-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides

A series of 4-(1-aryl-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzenesulfonamide derivatives (1–32) was synthesized and evaluated for its in vitro antimicrobial, antiviral and cytotoxic activities. Antimicrobial results indicated that compounds (11) and (18) were found to be the most effective ones. In general, the synthesized compounds were bacteriostatic and fungistatic in their action. The cytotoxic screening results indicated that the compounds were less active than the standard drug 5-fluorouracil (5-FU). None of the compounds inhibited viral replication at subtoxic concentrations. In general, the presence of a pyrimidine ring with electron releasing groups and an ortho- and para-substituted benzoyl moiety favored antimicrobial activities. The results of QSAR studies demonstrated the importance of topological parameters, valence zero order molecular connectivity index (⁰χ^v) and valence first order molecular connectivity index (¹χ^v) in describing the antimicrobial activity of synthesized compounds.     

Synthesis,anticancer activity and molecular docking studies of novel pyrido[1,2-a]pyrimidin-4-one derivatives

A series of novel triazolothione, thiadiazole, triazole, and oxadiazole-functionalized pyrido[1,2-a]pyrimidin-4-ones 6a–6l and 7a–7f were prepared, starting from pyridine derivatives 1a and 1b. All the compounds 6a–6l and 7a–7f were screened against four human cancer cell lines (HeLa, COLO205, Hep G2, and MCF 7), among which compounds 6d, 6h, 6j, 7b, and 7e showed promising anticancer activity. Molecular docking studies showed good binding energy and exhibited interactions and better lower free energy values, indicating more thermodynamically favored interaction.     

Synthesis,EGFR-TK inhibition and anticancer activity of new quinoxaline derivatives

Abstract

Ethyl 4-substituted-3-oxo-quinoxaline-2-carboxylates 3–5 were obtained via alkylation of ethyl 3-oxo-3,4-dihydroquinoxaline-2-carboxylate (1). Compound 1 was heterocyclized using hydrazines, ethylenediamine, and ethanolamine to give pyrazoloquinoxalines 6, 7, diazepinoquinoxaline 8, and oxazepinoquinoxaline 10. The quinoxaline-2-carboxamides 9, 11, 12 were prepared via condensation of compound 1 with different amines. Compound 1 was thiated using Lawesson’s reagent affording quinoxaline-3-thione 13, in fair yield. In addition, the reaction of 4-methyl-3-oxoquinoxaline 3 with some binucleophiles led to a series of new oxoquinoxaline derivatives 14–18. The molecular structure of compounds 1, 3, and 9 was confirmed by X-ray crystallography.

The anti-proliferative activity showed that among all the tested compounds, compounds 3, (IC₅₀ 2.51?±?3.0, 4.22?±?1.6 and 2.27?±?1.9?µM), 11 (IC₅₀ 1.32?±?2.61, 1.41?±?1.23 and 1.18?±?1.91?µM) and 17 (IC₅₀ 1.72?±?1.32, 1.85?±?0.94 and 1.92?±?4.83?µM) showed noteworthy anti-proliferative effects against the three cancer cell lines, HCT116, HePG2 and MCF7, respectively, compared to the reference drugs doxorubicin (IC₅₀ 1.41?±?0.58, 0.90?±?0.62 and 1.01?±?3.02?µM) and erlotinib (IC₅₀ 1.63?±?0.81, 1.57?±?0.62 and 1.49?±?0.54?µM). Compounds 3 (0.899?nM), 11 (0.508?nM) and 17 (0.807) showed strong EGFR inhibitory activity compared to Erlotinib (0.439?nM) and these results are in agreement with the docking study. These results suggest that compounds could probably be promising anticancer agents with EGFR inhibitory activity.     

Amide derivatives of 4-azaindole: Design,synthesis, and EGFR targeting anticancer agents

Abstract

A series of amide derivatives of azaindole-oxazoles (11a-n) were designed and synthesized and their structures were confirmed by ¹HNMR, ¹³CNMR and mass spectral analysis. Further, these derivatives were screened for their anticancer activity against human cancer cell lines viz; MCF7 (breast), A549 (lung) and A375 (melanoma). In vitro anticancer activity screening indicated that most of the hybrids exhibited potent inhibitory activities in a variety of cancer cell lines. Among the compounds 11d, 11e, 11f, 11j, 11k, 11l, 11m, and 11n were exhibited more potent activity than standard, in those mainly two compounds 11m and 11j were exhibited excellent activity in MCF-7 cell line with IC₅₀ values 0.034 and 0.036?µM. Moreover, all these compounds were carried out their molecular docking studies on EGFR receptor results indicated that two potent compounds 11m and 11j were strongly binds to protein EGFR (PDB ID: 4hjo). It was found that the energy calculations were in good agreement with the observed IC₅₀ values.     

In-silico profiling,design, molecular docking computation,and drug kinetic model evaluation of novel curcumin derivatives as potential anticancer agents

The alarming trend of leukemia cell lines that are multidrug-resistant has prompted scientists to scramble for effective new anticancer treatments. Therefore, it remains an intriguing scientific task to optimize curcumin by trying to introduce molecular alteration to its vital structure to improve the biological effect against the P388 cell line or get around resistance phenomena. Regardless of the wide range of medications that are now being studied, Prednisone remains the most important and efficient part of chemotherapy that the WHO recommends. This article discusses the QSAR-oriented model and in silico assessment of some potent curcumin derivatives' anticancer activity against the P388 cell line. The solidity and propensity for prediction of the model were ensured by using stringent validation procedures. The activity of these derivatives was shown to be unrelated to lipophilicity, while shorter N-N distances and short substituents result in quite bioactive molecules. This information was used to design potent molecules that demonstrate good quality as per the assessment based on the Lead-Like Soft rule is acceptable for drug-like molecules. Also, molecule d2 does not possess any toxic effects risk alerts, suggesting drug-adherent conduct. While Prednisone the reference drug has a toxicity risk alert in red, suggesting non-adherent conduct for Prednisone. Hence, the novel molecules are promising anticancer agents.     

Synthesis of spirooxindoles promoted by the deep eutectic solvent,ZnCl2+urea via the pseudo four-component reaction: anticancer,antioxidant, and molecular docking studies

Abstract

Various spirooxindoles (7a–c, 8a–c, 9a–c, and 10a–c) were efficiently synthesized using deep eutectic solvent ZnCl₂+urea and well characterized using IR, ¹H NMR, and ¹³C NMR spectroscopic techniques. The biological screening results showed that the compound 9a exhibited potent anticancer activity against MCF7 and HeLa cell lines with IC₅₀ values 6.47?±?0.01 and 9.14?±?0.32?µM, respectively. The compound 7c exhibited potent activity against the HeLa cell line with IC₅₀ value 6.81?±?0.01?µM. The compound 9a exhibited a potent antioxidant activity with IC₅₀ value 7.34?±?0.17?µM. The comparative molecular docking study against the cancer proteins EGFR and HER2 revealed that the EGFR was the best target protein receptor for the target compounds. Among all the compounds, the compound 9a exhibited the least binding energy ?10.72?kcal/mol against the protein EGFR (PDB ID: 4HJO).     

Synthesis,XRD, spectral,structural, quantum mechanical and anticancer studies of di(p-chlorobenzyl) (dibromo) (1, 10-phenanthroline) tin (IV) complex

The tin complex di (p-chlorobenzyl) (dibromo) (1, 10-phenanthroline) tin (IV) (4CLBR) was synthesised and subjected to characterization using spectroscopic techniques like FT-IR, Raman, ¹HNMR, ¹³CNMR, ¹¹⁹SnNMR, and crystallography. DFT method was used to compare theoretical and experimental results, and the theoretical method was done by the B3LYP/LanL2DZ. The VEDA programme package was used to design the entire vibrational spectral investigation. The Multiwfn software package was used to calculate the quantum chemical equations. A 2D network (C–H–Cl (C–Cl–H-benzyl, interactions forming a 2D network) and hydrogen bonding formed by bromine atoms such as C–H–Br (Sn–Br–H-Phen) were confirmed by X-rays as the complex and crystallisation. The crystal structure of the complex 4CLBR reveals that the tin atom is in a regular octahedral configuration. At the end of the day, anticancer activity has been investigated in this complex using a variety of cell lines, including PC3 (human prostate cancer cell), MCF7 (breast cancer cell), U937 (blood cancer cell), and U87 (brain cancer cell). The anticancer activity results clearly show that the complex 4CLBR and cisplatin have the same anticancer activity at concentrations of 15.6 g/ml against the U87 cell line.     

Synthesis,characterization, anticancer activity,and molecular docking of some new sugar hydrazone and arylidene derivatives

New sugar hydrazone moieties, their oxadiazoline derivatives, and arylidene analogues were prepared and chemically elucidated using spectroscopic analysis, such as nuclear magnetic resonance, for hydrogen ¹HNMR, carbon ¹³CNMR, elemental analysis, and Infrared (IR). The prepared compounds were purified and tested against breast cancer cells (MCF-7). Compounds 4c, 4d, 6b, and 6d exhibited moderate to very high anti-breast cancer activity, with a percentage of inhibition of 96.19%, 93.08%, 74.33%, and 86.05% respectively; the reference 5-fluorouracil had an inhibitory percentage of 96.02%.     

Solanopubamine,a rare steroidal alkaloid from Solanum schimperianum: Synthesis of some new alkyl and acyl derivatives,their anticancer and antimicrobial evaluation

Solanopubamine (3β-amino-5α, 22αH, 25βH-solanidan-23β-ol), a steroidal alkaloid was isolated from the alkaloidal fraction of Solanum schimperianum in significant yield. Its structure was established by IR, positive ESI-MS, 1D and 2D NMR. The presence of -3β-NH₂ and -23β-OH groups was achieved through methylation, acetylation or coupling with octadecanoic and undec-11-enoic acids to produce six derivatives (2–7). Their structures were confirmed by spectroscopic analyses. Solanopubamine and semi-synthetic analogs are investigated for their in vitro cytotoxicity against a panel of human cancer cell lines and anti-microbial activity. Solanopubamine showed good antifungal activity only against Candida albicans and C. tenuis with MIC of 12.5 μg/mL. Semi-synthesized compounds (2–7) have failed to show anti-tumor and anti-microbial activities.     

In vivo anticancer and histopathology studies of Schiff bases on Ehrlich ascitic carcinoma cells: 1st Cancer Update

Three Schiff bases in two different concentrations were evaluated for their anti-tumor activity against Ehrlich ascites carcinoma (EAC) bearing Swiss albino mice. The in vivo anti-tumor potency of Schiff bases was assessed by measuring the increase in mean survival time of the drug treated over untreated control mice and treated standard (cisplatin) mice. Their toxicity was assessed in vivo in normal, standard, and EAC-bearing mice by measuring the drug-induced changes in biochemical as well as hematological parameters. The histopathology studies to assess the toxicity of these compounds on vital organs also have been studied. Among the three Schiff bases studied, 4-({[3-(4-fluorophenyl)-1H-pyrazol-4-yl]methylene}amino)-5-[(2-methylphenoxy)methyl]-1,2,4-triazole-3-thiol (SB-3) at an optimal dose of 100 mg/kg body weight was found to enhance the mean survival time of infected mice. Deviated hematological parameters and mean survival time in tumor bearing mice were found to be significantly restored towards normal after treatment with SB-3 100 mg/kg body weight of mice. The ALP and SGOT values were found to approach the normal range. A:G ratios also did not deviate from normal on treatment with SB-3. The histopathology studies revealed only mild hepatotoxicity and nephrotoxicity when compared to the normal and standard. The splenic cellularity also did not show much variation from normal. SB-3 at a prime dose of 100 mg has shown promising anticancer activity in vivo against EAC when compared to standard drug with minimum toxic effects.     

Synthesis,antimicrobial and cytotoxic activity of novel azetidine-2-one derivatives of 1H-benzimidazole

A series of 1-methyl-N-[(substituted-phenylmethylidene)-1H-benzimidazol-2-amines (4a–4g) were prepared via the formation of 1-methyl-1H-benzimidazol-2-amine (3), which was prepared by the cycloaddition of o-phenylenediamine (1) with cyanogen bromide in the presence of aqueous base followed by N-methylation with methyl iodide in the presence of anhydrous potassium carbonate in dry acetonitrile. Moreover, the four-membered β-lactam ring was introduced by the cycloaddition of 4a–4g and chloroacetyl chloride in the presence of triethylamine catalyst to give 3-chloro-1-(1-methyl-1H-benzimidazol-2-yl)-(4′-substituted)-phenylazetidin-2-one 5a–5g. A total of 14 compounds were synthesized and characterized by IR, ¹H NMR, ¹³C NMR and Mass spectral technique, in addition they were evaluated for anti-bacterial and cytotoxic properties. Among the chemicals tested 4a, 4b, 5a, 5b, 5g exhibited good antibacterial activity and 5f, 5g shown good cytotoxic activity in vitro.     

Synthesis,structure, anticancer activities,and DNA-binding properties of a 1-D polymeric copper(II) complex alternately bridged by oxamide and terephthalate

A 1-D polymeric copper(II) complex alternately bridged by N,N′-bis(N-hydroxyethylaminopropyl)oxamide (heap^2?) and terephthalate (tpa^2?), [Cu₂(heap)(tpa)] _n , has been synthesized and characterized by single-crystal X-ray diffraction. The crystal structure reveals that the asymmetric unit of the copper(II) polymer is half a dinuclear copper(II) complex, [Cu₂(heap)(tpa)], in which Cu(II) is located in a square-pyramidal coordination environment. Separations of Cu(II) through heap^2? and tpa^2? bridges are 5.2459(6) and 11.1375(6)?Å, respectively. The complex chains, accompanied with glide planes parallel to the a0c plane, can be classified to two groups according to their extending direction. Hydrogen bonds occur between a complex chain and any adjacent ones in the other orientation. Consequently, a 3-D supramolecular network is completed. The polymeric copper(II) complex exhibits potent anticancer activities against human hepatocellular carcinoma cell SMMC-7721 and human lung adenocarcinoma cell A549 tested by sulforhodamine B assays. The interactions of the polymeric copper(II) complex with herring sperm DNA (HS-DNA) are investigated by using electronic absorption titration, fluorescence titration, electrochemical titration, and viscometry measurements. The results suggest that the polymeric copper(II) complex interacts with HS-DNA via intercalation with intrinsic binding constant of 1.8?×?10^6?(mol?L^?1)^?1.