Synthesis,in Vitro,and in Vivo Biological Evaluation and Molecular Docking Analysis of Novel 3‐(3‐oxo‐substitutedphenyl‐3‐)4‐(2‐(piperidinyl)ethoxy)phenyl)propyl)‐2H‐chromen‐2‐one Derivatives as Anti‐breast Cancer Agents

The analogs of coumarin–chalcones have been reported to exhibit antineoplastic, anti‐allergic, antihepatoprotective, and estrogenic activity. Herein, we have reported 3‐(3‐oxo‐substitutedphenyl‐3‐)4‐(2‐(piperidinyl)ethoxy)phenyl)propyl)‐2H‐chromen‐2‐one derivatives as a new class of compounds that exhibit selectivity for ER‐α binding along with antiproliferative and cytotoxic activity on human breast cancer cell line. The active compounds which show prominent activity against estrogen receptor‐alpha‐positive (ER+) human breast cancer cell lines MCF‐7 and Zr‐75‐1 are subjected to in vivo screening. The Glide XP docking was performed for designed scaffold to optimize its structural requirement for ER‐α inhibition.     

Novel 3‐substituted N‐methylcarbazole–imidazolium salt derivatives: Synthesis and cytotoxic activity

A series of novel 3‐substituted N‐methylcarbazole–imidazolium salt derivatives has been prepared and evaluated in vitro against a panel of tumor cell lines (Hep G‐2, Hela and PC12). The results suggest that the presence of substituted 2‐methyl‐imidazole or imidazole ring and substitution of the imidazolyl‐3‐position with a naphthylacyl or 4‐bromophenacyl group were important for improving cytotoxic activity. Compounds 17 , 18 , 27, and 28 with 4‐bromophenacyl and naphthylacyl groups displayed good activities with IC₅₀ values of 0.09–7.20 μm against three tumor cell lines investigated and more active than DDP. Compound 35 exhibited cytotoxic activity selectively against Hela cell.     

Isolation,modification and cytotoxic evaluation of flavonoids from Rhododendron hainanense

Objectives The aim of this study was to search for antitumour activity of flavonoid compounds. The cytotoxic activity of these compounds in vitro was evaluated against the human leukaemia (HL‐60) and human hepatoma (SMMC‐7721) cell lines. Methods Eight natural flavonoids ( 1 – 8 ) were isolated from the aerial parts of Rhododendron hainanense and a series of modified flavonoid derivatives ( 9 – 18 ) were obtained from the natural product matteucinol ( 1 ), using simple synthetic methods. Antitumour inhibitory activity of these flavonoids was assessed using the sulforhodamine B method. Key findings Most of the compounds exhibited good pharmacological activity and the preliminary structure–activity relationships were described. Within the series of flavonoid derivatives in this study, compounds 3 (2,3‐dihydro‐5‐hydroxy‐7‐methoxy‐2‐(4‐methoxyphenyl)‐6,8‐dimethyl‐4H‐1‐benzopyran‐4‐one) and 16 (5‐hydroxy‐7, 4′‐dimethoxy‐6, 8‐dimethylflavan) exhibited strong inhibitory activity against the HL‐60 cell line with IC50 values (the drug concentration that resulted in a 50% reduction in cell viability or inhibition of the biological activity) of 15.2 and 13.2 µm , respectively. Conclusions Renewed attention to flavonoid derivatives revealed the possibility that compounds 3 and 16 could be considered as lead compounds for the development of new antitumour agents. Our results have not only enriched the family of active flavonoids from natural sources, but have encouraged the synthesis of flavonoid analogues for improving cytotoxic activity.     

Synthesis of new arylisoxazole–oxindole conjugates as potent antiproliferative agents

A new series of arylisoxazole–oxindole derivatives ( 6a–r ) were synthesized and evaluated for their antiproliferative activity against human cancer cell lines including non‐small cell lung (A549), cervical (HeLa), breast (MCF‐7), and prostate (DU‐145) cancer cell lines. The synthesized compounds ( 6a–r ) demonstrated excellent to moderate cytotoxicity with IC₅₀ values ranging from 0.82 to 3.69 μm . Some new compounds ( 6m–r ) exhibited profound cytotoxicity better or similar to positive control. More particularly, the compound 6q possesses donating substituent like methoxy group presented at 5‐position on D ring exhibited remarkable antiproliferative activity against A‐549 (lung cancer) with an IC₅₀ value 0.82 μm . Further studies to determine the mechanistic aspects of these conjugates are under progress.     

Synthesis and in‐vitro Cytotoxic Evaluation of Novel Pyridazin‐4‐one Derivatives

A new series of N‐aryl‐4‐oxo‐1,4‐dihydro‐pyridazine‐3‐carboxylic acids has been synthesized by condensation of aryldiazonium with 4‐hydroxy‐6‐methyl‐2‐pyrone. Some of these compounds exhibited in‐vitro cytotoxic activity with moderate to excellent growth inhibition against the murine P815 mastocytoma cell line. Compound 5b showed an important cytotoxic activity against cell line P815 (IC₅₀ = 0.40 μg/mL).     

One‐Pot Laccase‐Catalysed Synthesis of 5,6‐Dihydroxylated Benzo[b]furans and Catechol Derivatives,and Their Anticancer Activity

A commercial laccase, Suberase® from Novozymes, was used to catalyse the synthesis of 5,6‐dihydroxylated benzo[b]furans and catechol derivatives. The yields were, in some cases, similar to or better than that obtained by other enzymatic, chemical or electrochemical syntheses. The synthesised derivatives were screened against renal (TK10), melanoma (UACC62), breast (MCF7) and cervical (HeLa) cancer cell lines. GI₅₀, TGI and LC₅₀ are reported for the first time. Anticancer screening showed that the cytostatic effects of the 5,6‐dihydroxylated benzo[b]furans were most effective against the melanoma (UACC62) cancer cell line with several compounds exhibiting potent growth inhibitory activities (GI₅₀ = 0.77–9.76 µM), of which two compounds had better activity than the anticancer agent etoposide (GI₅₀ = 0.89 µM). One compound exhibited potent activity (GI₅₀ = 9.73 µM) against the renal (TK10) cancer cell line and two exhibited potent activity (GI₅₀ = 8.79 and 9.30 µM) against the breast (MCF7) cancer cell line. These results encourage further studies of the 5,6‐dihydroxylated benzo[b]furans for their potential application in anticancer therapy.     

Novel quinazolin‐4(3H)‐one linked to 1,2,3‐triazoles: Synthesis and anticancer activity

In this work, a wide range of novel quinazolin‐4(3H)‐one linked to 1,2,3‐triazoles was designed, synthesized, and evaluated against a panel of three human breast (MDA‐MB‐231, MCF‐7, T‐47D), lung (A549), and prostate (PC3) cancer cell lines. Our results revealed that the anticancer activity of the synthesized compounds was selectively affected by the presence of methoxy group on the linker between quinazolinone and 1,2,3‐triazole moieties. According to the calculated IC₅₀ values, compounds 6q , 6w , and 6x showed good cytotoxicity against breast cancer cell lines even more effective than the reference drug, etoposide. Compounds 6q and 6u were found to be potent compounds against A549, non‐small‐cell lung cancer (NSCLC), comparing with erlotinib. Also, the morphological analysis by acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that potent compounds induced apoptosis in human cancer cell lines. Molecular docking studies were performed to clarify the inhibition mode of compounds 6g , 6u , 6w , and 6x over the EGFR active site. The most promising compounds, 6q and 6u , possessing 3‐methoxy group were well oriented to the gatekeeper hydrophobic pocket of EGFR active site and interact well with Ala719, Val702, and Leu820 through hydrophobic interaction.     

Novel Thiophenes,Thienopyrimidines, and Triazolothienopyrimidines for the Evaluation of Anticancer and Augmentation Effects of γ‐Radiation

New derivatives of thiophenes 2 , 12 , iminoaminothieno[2,3‐d]pyrimidines 3 , 5 , and 6 , triazolothieno[2,3‐d]pyrimidines 8–11 , pyrazolo‐ and triazinothieno[2,3‐d]pyrimidines 4 , 7 , respectively, have been prepared by different synthetic procedures. Structure elucidation of the newly synthesized compounds was carried out via elemental analyses and spectral data. The antitumor activity of compounds 2 , 3 , and 9–12 was evaluated against in‐vitro cell lines (HEPG‐2 and MCF‐7). Compounds 2 , 3 , 10 , 11 , and 12 showed significant in‐vitro cytotoxic activity against hepatocellular carcinoma (HEPG‐2) compared to the reference drug Doxorubicin. Compound 2 showed significant in‐vitro cytotoxic activity against breast cancer (MCF‐7) cells compared to the reference drug Doxorubicin. The augmenting effect of γ‐radiation was assessed; here, compounds 2 , 3 , 10 , and 11 showed the most potent in‐vitro anticancer activity.     

Cytotoxic and trypanocidal activities of cinchona alkaloid derivatives

A series of 27 cinchona alkaloid derivatives ( 1f–w , 2a–e and 3a–d ) were investigated for their cytotoxic and trypanocidal activities using seven different cancer cell lines (KB, HeLa, MCF‐7, A‐549, Hep‐G2, U‐87 and HL‐60), two normal cell lines (HDF and CHO) and bloodstream forms of Trypanosoma brucei brucei, respectively. Four compounds ( 1u , 1w , 2e and 3d ) were identified with promising cytotoxic activity with 50% growth inhibition (GI₅₀) values below 10 μM. Two ( 2e and 3d ) of the four compounds also exhibited potent anti‐trypanosomal activity with GI₅₀ values of 0.3–0.4 μM. All four active compounds represented derivatives modified at their C‐9 hydroxy group. With respect to anti‐proliferative activity and selectivity, 2e (epi‐N‐quinidyl‐N′‐bis(3,5‐trifluoromethyl)phenylthiourea) proved to be the most promising derivative for both cancer cells and bloodstream forms of T. b. brucei. The cytotoxic activity of compounds 1u , 1w , 2e and 3d was attributed to their ability to induce apoptosis in cancer cells. The results demonstrate the potential of cinchona alkaloid derivatives as novel anti‐cancer and anti‐trypanosome drug candidates.     

Synthesis and In‐Vitro Antitumor Activities of Some Mannich Bases of 9‐Alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones

A novel series of 2‐substituted aminomethyl‐9‐alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones 5a – q was synthesized via aminomethylation of 9‐alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones 4a – e with hydrochlorides of the respective amines 6a – m . The structures of these newly synthesized compounds were characterized by ¹H‐NMR, MS, and elemental analysis. All the compounds were tested for their cytotoxic activity in vitro against four human tumor cell lines including human non‐small lung cancer cells (A549), human gastric adenocarcinoma (SGC), human colon cancer cell (HCT116), human myeoloid leukemia cells (K562), and one multi‐drug resistant subline (KB‐VCR). Most compounds showed moderate to potent cytotoxic activity against the tested cell lines. Preliminary mechanism research indicated that the most promising compound, 2‐diethylaminomethyl‐9‐methyl‐1,2,3,4‐tetrahydrocarbazole‐1‐one 5c , exhibited a potential inhibitory effect against microtubule.     

Novel naphthalimide-benzoic acid conjugates as potential apoptosis-inducing agents: design, synthesis, and biological activity

A series of novel naphthalimide derivatives with 4‐[4‐(3,3‐diphenylallyl)piperazin‐1‐yl]benzoic acid as side chain were designed and synthesized. Their antitumor activities were evaluated against a variety of cancer cell lines in vitro. Preliminary results showed that most of the derivatives had cytotoxic activity comparable with that of amonafide, with IC₅₀ values of 10⁻⁶–10⁻⁵ m . Interestingly, compound 12e had the unique antitumor activity against MCF‐7 among the cancer cell lines tested. More importantly, flow cytometric analysis indicated that compared with amonafide, the target compounds could effectively induce G₂/M arrest and progress to apoptosis in HL‐60 cells after double staining with annexin V–FITC and propidium iodide. The present work provided a novel class of naphthalimide‐based derivatives with potential apoptosis‐inducing and improved antitumor activity for further optimization.     

Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐d]pyrimidin‐4(3H)‐one derivatives

5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l , showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.     

Design and synthesis of 2‐phenyl benzimidazole derivatives as VEGFR‐2 inhibitors with anti‐breast cancer activity

Three new series of 2‐phenyl benzimidazole‐based derivatives were designed, synthesized, and evaluated for their in vitro cytotoxic activity against breast cancer (MCF‐7) cell lines. Three compounds 8 , 9 , and 15 showed high cytotoxic activities, with IC₅₀ values of 3.37, 6.30, and 5.84 μM, respectively, while they showed comparable cytotoxicity to the standard drug doxorubicin against human normal cells, including nontumorigenic breast epithelial cell line (MCF‐10F), skin fibroblast cell line (BJ), and lung fibroblast cell line (MRC‐5). Six of the synthesized compounds were screened against vascular endothelial growth factor receptor 2 (VEGFR‐2) where compounds 8 , 9 , 12 , and 15 exhibited an outstanding potency in comparison with sorafenib, with IC₅₀ values of 6.7–8.9 nM. Molecular docking study assessed the good binding patterns of the most potent compounds with the reported conserved amino acids of VEGFR‐2 active site.     

Synthesis and Antimicrobial Evaluation of 6‐Alkylamino‐N‐phenylpyrazine‐2‐carboxamides

This work presents synthesis and antimicrobial evaluation of nineteen 6‐alkylamino‐N–phenylpyrazine‐2‐carboxamides. Antimycobacterial activity was determined against Mycobacterium tuberculosis H37Rv, M. kansasii and two strains of M. avium. Generally, the antimycobacterial activity increased with prolongation of simple alkyl chain and culminated in compounds with heptylamino substitution ( 3e , 4e ) with MIC = 5–10 μm against M. tuberculosis H37Rv. On the contrary, derivatives with modified alkyl chain (containing e.g. terminal methoxy or hydroxy group) as well as phenylalkylamino derivatives were mainly inactive. The most active compounds (with hexyl to octylamino substitution) were evaluated for their in vitro activity against drug‐resistant strains of M. tuberculosis and possessed activity comparable to that of the reference drug isoniazid. None of the tested compounds were active against M. avium. Some derivatives exhibited activity against Gram‐positive bacteria including methicillin‐resistant Staphylococcus aureus (best MIC = 7.8 μm ), while Gram‐negative strains as well as tested fungal strains were completely unsusceptible. Active compounds were tested for in vitro toxicity on various cell lines and in most cases were non‐toxic up to 100 μm .     

Design and synthesis of new 2‐anilinoquinolines bearing N‐methylpicolinamide moiety as potential antiproliferative agents

A series of new 2‐anilinoquinolines 6a – o possessing the substantial N‐methylpicolinamide motif at C5 has been designed and synthesized as sorafenib analogs. The antiproliferative activities of the target compounds were preliminarily appraised against a panel of three human cancer cell lines (MCF‐7, SK‐BR3, and HCT116), and a selected array was further tested over a panel of approximately 60 cancer cell lines at NCI at 10 μM concentration. Interestingly, compounds 6c , 6d , 6j , 6k , and 6l showed promising selective anticancer activities (growth inhibition >80%) toward certain cancer cells at 10 μM testing dose. Compounds 6d and 6j were advanced to five‐dose testing mode to determine their GI₅₀ values and compared with our previously reported ureidoquinoline B and sorafenib as reference compounds. The 4‐chloro‐3‐trifluoromethylaniline derivative 6j manifested superior potency than both compound B and sorafenib over eleven and eight cell lines, respectively. It showed GI₅₀ values of 0.36, 0.66, 0.68, and 0.60 μM against the breast MDA‐MB‐468, renal A498, and melanoma SK‐MEL‐5 and UACC‐62 cell lines, respectively. Moreover, both 6d and 6j exerted low cytotoxic effects against HFF‐1 normal cell line. Furthermore, compounds 6d and 6j were tested against both B‐Raf^V600E and C‐Raf kinases and displayed modest inhibitory activities, which were justified by molecular docking study. Compound 6j could serve as a promising candidate for further development of potent anticancer chemotherapeutics.     

Synthesis,molecular modeling,in vivo study,and anticancer activity of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen

A new series of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen ( 7a–m ) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier‐transform infrared spectroscopy, ¹H‐nuclear magnetic resonance (NMR), ¹³C‐NMR, and high‐resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase‐2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU‐145, and LNCaP) using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU‐145 and LNCaP cancer cell lines with IC₅₀ values of 26.0, 34.5, and 48.8 μM, respectively. Compounds 7b , 7k , and 7m showed anticancer activity against cancer cell lines PC3 and DU‐145 with IC₅₀ values of 43.0, 36.5, 29.3 μM and 49.8, 49.1, 31.6 μM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC₅₀ values of 43.4 and 34.5 μM, respectively. To assess the biodistribution in mice of IRDye800, dye‐labeled compound 7a or 100 μM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.     

3‐Aminomethyl pyridine chalcone derivatives: Design,synthesis, DNA binding and cytotoxic studies

Herein we report design, synthesis, and anticancer activity of compounds 6a–h and 11a–j . Compounds 6a–f were designed based on 3‐aminomethyl pyridine attached to different acetamide derivatives and in compounds 6g–h it was attached to coumarin moiety. Coumarin containing compounds 6g–h showed very poor anticancer activity against both A549 (Lungs cancer cell line), and MCF‐7 (Breast cancer cell line) cell lines in MTT assay. Compounds 11a–j were designed as derivatives of 3‐aminomethyl pyridine and 4‐amino chalcones. A series of chalcone derivatives of 3‐aminomethyl pyridine 11a–j have been synthesized and screened for their in vitro anticancer activity and DNA binding affinity. Most of the compounds showed very good antimitotic activity against A549 cell line as compared to fluorouracil. Compounds 11g and 11i were selected for DNA‐binding studies as they showed excellent activity against cancer cell lines in MTT assay. CT‐DNA binding affinity of compounds 11g and 11i have been investigated by UV based DNA titration and fluorescence emission study against DNA‐EtBr complex. Interestingly, compound 11i has displayed excellent antiproliferative activity, with IC₅₀ 0.0067 ± 0.0002 μm , against MCF‐7 cell line. Compound 11i has been studied for its cytotoxicity using MTT, LDH, as well as EtBr/AO assay and was found to induce apoptosis in the cancerous cell line.     

Synthesis and biological evaluation of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione as antimycobacterial agents

Resistance among dormant mycobacteria leading to multidrug‐resistant and extremely drug‐resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione derivatives ( 4a–5c ) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC₅₀) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram‐negative and Gram‐positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 μg/ml against THP‐1, A549, and PANC‐1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection.