Synthesis of some pyrazolines and pyrimidines derived from polymethoxy chalcones as anticancer and antimicrobial agents

The synthesis of a series of certain polymethoxy chalcones and some derived pyrazole, pyrimidine, and thiazolopyrimidine ring structures is reported. Eleven compounds 4 , 6 , 9 , 11 , 14–17 , 22 , 24 , and 25 were selected by the National Cancer Institute (NCI) to be screened for their in‐vitro anticancer activity, whereas all the synthesized compounds were evaluated for their in‐vitro antimicrobial activity. Compounds 4 , 6 , and 11 were found to possess a significant broad spectrum antitumor potential against most of the tested subpanel tumor cell lines. The pyrazolines 4 and 6 displayed remarkable growth inhibitory activities (GI₅₀ MG‐MID values of 2.10 and 1.38 µM, respectively), together with moderate cytostatic effects (TGI MG‐MID values of 47.9 and 42.7 µM, respectively). Meanwhile, the pyrimidin‐2‐one 11 showed a noticeable overall tumor growth inhibitory activity, together with high cytostatic and cytotoxic efficacies (GI₅₀, TGI and LC₅₀ MG‐MID values of 3.39, 17.4, and 61.7 µM, respectively). On the other hand, compounds 3 , 4 , 13 , 15 , 19 , 20 , and 23 were found to be the most active antimicrobial members in this investigation with a broad spectrum of activity. Compound 23 was four times superior to ampicillin against Pseudomonas aeruginosa. The best antifungal activity was demonstrated by compounds 4 , 5 , and 11 which possessed almost half the activity of clotrimazole against Candida albicans. Collectively, the obtained biological results suggest that compound 4 could be considered as a possible dual antimicrobial‐anticancer agent.     

Adlumiceine methyl ester,a new alkaloid from Fumaria vaillantii

A new alkaloid, adlumiceine methyl ester (1), together with two known alkaloids, parfumine (2) and N-methylhydrastine methyl ester (3), was isolated from aerial parts of Fumaria vaillantii. The structures of compounds were determined by 1D/2D NMR and MS data. All three compounds were tested for cytotoxic activity against PC3 and MCF7 cell lines using Alamar blue assay. The tested compounds showed no significant cytotoxic activity (IC₅₀>50 μM) against PC3 and MCF7 cell lines.     

Synthesis,in‐vitro Antimicrobial and Cytotoxic Studies of Novel Azetidinone Derivatives

Developing novel antimicrobial drugs is increasingly important in the modern pharmaceutical industry. A series of novel 3‐chloro‐4‐[4‐(2‐oxo‐2H‐chromen‐4‐ylmethoxy)phenyl]‐1‐phenylazetidin‐2‐ones 5a–o have been synthesized from 4‐bromomethylcoumarins 1a–e and 4‐aryliminomethyl‐phenols 3a–c . These compounds were screened for their in‐vitro antibacterial activity against two Gram‐positive (Staphylococcus aureus and Vancomycin resistant enteroccoccus) and two Gram‐negative (Escherichia coli and Shigella dysentery) bacterial strains and antifungal activity against Aspergillus fumigatus, Candida albicans, and Penicillium. Results revealed that compounds 5c , 5f , 5h , 5j , and 5m showed excellent activity against a panel of microorganisms. The brine‐shrimp bioassay was also carried out to study their in‐vitro cytotoxic properties and two compounds, 5h and 5m , possessing LD₅₀ = 7.154×10^–4 M and 5.782×10^–4 M, respectively, displayed potent cytotoxic activity against Artemia salina. The presence of a chlorine group in the coumarin moiety, its effect on their antibacterial, antifungal, and cytotoxic activities is discussed. All newly synthesized compounds were characterized by elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR, and MS.     

Antibacterial and cytotoxic activity from the extract and fractions of a marine derived bacterium from the Streptomyces genus

Abstract

Context: Marine natural products are a rich source of potent, selective, and structurally novel compounds. Marine bacteria are considered the most promising source of biologically active compounds which can be applied to treat a wide range of diseases.

Objective: The current study was designed to establish the bases for a future marine exploration in the Ecuadorian coast based on the molecular identification of a marine bacterium and its potential use as an antibacterial or cytotoxic compounds source.

Materials and methods: Isolation and characterization of the marine bacterium were carried out through microbiological methods from desiccated sediment. Molecular identification was made by means of 16S rDNA analysis. MIC was measured by the microdilution broth method against six pathogenic bacteria: two Gram positive and four Gram negative strains. Cytotoxicity was evaluated by Crystal violet assay against breast adenocarcinoma (MCF7) and ductal carcinoma (T47D and ZR-75-30).

Results: Our present study has shown that EtOAc extract and fraction A1 obtained from marine Streptomyces sp. revealed the maximal antibacterial and cytotoxic activity. Enterococcus faecalis was found to be more sensitive strain (MIC 0.78?μg/ml) than the other five bacteria tested. ZR-75-30 and T47D cell lines were found to be more sensitive (IC₅₀ value, 31.88?±?0.05 and 68.35?±?0.12?μg/ml) than adenocarcinoma MCF7 (IC₅₀ value was 83.65?±?0.06?μg/ml).

Discussion and conclusion: The results obtained herein indicate that EtOAc extract of Streptomyces sp. has shown a strong antibacterial activity as well as moderate cytotoxic activity which make it a good candidate for metabolite isolation.     

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.     

Anionic chlorido(triphenyl)tin(IV) bearing N‐phthaloylglycinato or 1,2,4‐benzenetricarboxylato 1,2‐anhydride ligands: potential cytotoxic and apoptosis‐inducing agents against several types of cancer

Two ionic triphenyltin(IV ) chloride carboxylate compounds of the formula [NHE t₃][Ph₃SnCl(L)] [LH  = N‐phthaloylglycine (P‐GlyH), 1 ; 1,2,4‐benzenetricarboxylic 1,2‐anhydride (BTCH ), 2 ] were tested for the in vitro activity against 518A2 (melanoma), FaDu (head and neck carcinoma), HT ‐29 (colon cancer), MCF ‐7 (breast carcinoma), and SW 1736 (thyroid cancer) cell lines. The ammonium salts of the carboxylic acids are found to be not active, while anionic [Ph₃SnCl(L)]^? exhibited high cytotoxicity in nM range, both higher activity and selectivity than cisplatin. Compounds 1 and 2 are inducing apoptosis, which was proved with the morphological and biochemical features such as membrane blebbing, translocation of phosphatidylserine, and DNA fragmentation. Thus, accumulation of cells in sub‐G1 phase is observed. Both anionic organotin(IV ) compounds showed potent cytotoxic and apoptotic properties against five cancer cell lines of various histogenetic origin.     

Synthesis and Biological Evaluation of Novel Pyrazoles and Pyrazolo[3,4‐d]pyrimidines Incorporating a Benzenesulfonamide Moiety

Synthesis and biological evaluation of novel pyrazoles and pyrazolo[3,4‐d]pyrimidines are reported. Fourteen compounds were selected by the NCI and tested for their preliminary in‐vitro anticancer activity, whereas all the synthesized compounds were evaluated for their in‐vitro antimicrobial activity. Compound 12a was proven to possess the highest anticancer activity with a broad spectrum profile. It showed particular effectiveness towards leukemia HL‐60 (TB), K‐562, non‐small cell lung cancer NCI‐H23, and colon cancer HT 29, KM 12 cell lines (GI₅₀ = 6.59, 4.44, 1.37, 3.33, and 9.63 μM, respectively). Out of the synthesized compounds, thirteen derivatives were found to display pronounced antimicrobial activity especially against P. aeruginosa. Compounds 2c , 5b , 10 , 11b , 17b , 18b , and 19 were proven to be the most active with a broad spectrum of activity. Compound 19 was found to be equipotent to ampicillin against B. subtilis, whereas compounds 11b and 19 were four times superior to ampicillin against P. aeruginosa, while compounds 5b and 18b were equipotent to ampicillin against the same organism. Moreover, compounds 2c , 10 , and 11b were nearly equipotent to ampicillin against E. coli. On the other hand, compounds 2c , 5b , 10 , 11a , 17b , and 18b exerted nearly half the activity of clotrimazole against C. albicans.     

Synthesis and Biological Evaluation of Distamycin Analogues – New Potential Anticancer Agents

Eight of analogues of distamycin, potential minor‐groove binders, were synthesized and tested for in‐vitro cytotoxicity towards human breast cancer cells MCF‐7 and MDA‐MB‐231. The method of synthesis is simple and convenient. All of the compounds 1 – 8 showed antiproliferative and cytotoxic effects against both cell lines in the range 3.47 to 12.53 μM for MDA‐MB‐231 and 4.35 to 12.66 μM for MCF‐7. All compounds demonstrated activity against DNA topoisomerases I and II at a concentration of 50 μM. The ethidium bromide assay showed that these compounds bind to plasmid pBR322, yet weaker than distamycin. Further investigations concerning the mechanism of cytotoxicity are now in progress, but the IC₅₀ values suggest that synthetic distamycin analogues with a free amino group, 3 – 4 and 7 – 8 , can serve as potential carriers of strong acting elements, e. g. alkylating groups.     

Design,synthesis and pharmacophoric model building of new 3‐alkoxymethyl/3‐phenyl indole‐2‐carboxamides with potential antiproliferative activity

Novel 3‐alkoxymethyl/3‐phenyl indole‐2‐carboxamide derivatives were synthesized and evaluated for their anticancer activity. Most of the tested compounds showed moderate to excellent activity against the tested cell lines (MCF7 and HCT116). 3‐Phenyl substitution on indole with p‐piperidinyl phenethyl 24a and p‐dimethylamino phenethyl 24c exhibited anticancer activity against MCF7 with IC₅₀ of 0.13 and 0.14 μm , respectively. Further mechanistic study of the most active compounds through their action on cell cycle showed disturbance in cell cycle progression and cell cycle arrest. For future development of this series of compounds, pharmacophore study was conducted which indicated that the enhancement of the activity could be achieved through the addition of acceptor or donating groups to the already‐present indole nucleus.     

Design,synthesis, and biological evaluation of 1,8-naphthyridine glucosamine conjugates as antimicrobial agents

In the quest for discovering potent antimicrobial agents with lower toxicity, we envisioned the design and synthesis of nalidixic acid-D-(+)-glucosamine conjugates. The novel compounds were synthesized and evaluated for their in vitro antimicrobial activity against Gram positive bacteria, Gram negative bacteria and fungi. Cytotoxicity using MTT assay over L6 skeletal myoblast cell line, ATCC CRL-1458 was carried out. In vitro antimicrobial assay revealed that 1-ethyl-7-methyl-4-oxo-N-(1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranose-2-yl)-[1,8]-naphthyridine-3-carboxamide (5) and 1-ethyl-7-methyl-4-oxo-N-(2-deoxy-D-glucopyranose-2-yl)-[1,8]-naphthyridine-3-carboxamide (6) possess growth inhibitory activity against resistant Escherichia coli NCTC, 11954 (MIC 0.1589 mM) and Methicillin resistant Staphylococcus aureus ATCC, 33591 (MIC 0.1589 mM). Compound (5) was more active against Listeria monocytogenes ATCC 19115 (MIC 0.1113 mM) in comparison with the reference nalidixic acid (MIC 1.0765 mM). Interestingly, compound (6) had potential antifungal activity against Candida albicans ATCC 10231 (MIC <0.0099 mM). Remarkably, the tested compounds had low cytotoxic effect. This study indicated that glucosamine moiety inclusion into the chemical structure of the marketed nalidixic acid enhances antimicrobial activity and safety.     

New pyrimidinone and fused pyrimidinone derivatives as potential anticancer chemotherapeutics

A series of novel substituted pyrimidinones and fused pyrimidinones (compounds 3 – 18 ) were synthesized starting with oxiranylmethanone 2 . The in vitro cytotoxicity against a human breast adenocarcinoma (MCF‐7) cell line was investigated and most of the tested compounds showed potent cytotoxic activity against the MCF‐7 cell line comparable to the activity of the commonly used anticancer drug cisplatin. Treatment of MCF‐7 cells with increasing doses (2, 5, 10, and 20 µg/mL) of the tested compounds revealed that the activity of superoxide dismutase and the level of hydrogen peroxide were significantly increased, while the activities of catalase and glutathione peroxidase and the levels of reduced glutathione were significantly lowered compared with control MCF‐7 cells. In general, derivatives 11 and 16 revealed the highest anticancer activity among the tested compounds.     

Synthesis and biological evaluation of novel imidazopyrimidin‐3‐amines as anticancer agents

Groebke–Blackburn–Bienayme reaction has been utilized for the synthesis of new imidazo[1,2‐a]pyrimidine derivatives as novel anticancer agents. The cytotoxic activities of compounds were evaluated against human cancer cell lines including MCF‐7, T‐47D, and MDA‐MB‐231, compared with etoposide as the standard drug. Among the tested compounds, hydroxy‐ and/or methoxy‐phenyl derivatives ( 6a–c and 6k ) with IC₅₀ values of 6.72–14.36 μm were more potent than etoposide against all cell lines. The acridine orange/ethidium bromide double staining and DNA fragmentation studies demonstrated that the cytotoxic effect of 3‐hydroxy‐4‐methoxyphenyl derivative 6c is associated with apoptosis in cancer cells.     

Synthesis and Antibacterial Activity of a Novel Series of 2,3‐Diaryl‐substituted‐imidazo(2,1‐b)‐benzothiazole Derivatives

Benzothiazole and imidazole compounds are extensively studied heterocyclics due to their wide spectrum of bioactivities. Among them, the imidazo(2,1‐b)‐benzothiazole derivatives are pharmacologically important because of their immunostimulant, anti‐inflammatory, antifungal, antimicrobial, antitumor, and other activities. In the present research work, a novel series of 2,3‐diaryl‐substituted imidazo(2,1‐b)‐benzothiazoles 13a–o have been synthesized by reaction of substituted 2‐aminobenzothiazoles 1–8 and an appropriately substituted α‐bromo‐1‐(4′′‐substituted)‐phenyl‐2‐(4′‐substituted)‐phenyl‐1‐ethanones 9–12 in the presence of anhydrous acetonitrile. They were characterized by physicochemical, elemental, and spectral (IR, ¹H‐NMR, and Mass) data. All the synthesized compounds were screened for their in‐vitro antibacterial activity against Gram‐positive, Gram‐negative bacteria. The investigation of antibacterial screening data revealed that most of the compounds tested have demonstrated congruent activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa as compared with the standard ampicillin. Among the series, compounds 13d , 13h , and 13m exhibited excellent an antibacterial activity profile as compared with the standard. In summary, preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activities and they warrant more consideration as prospective antimicrobials.     

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.     

Synthesis and <Emphasis Type="Italic">in Vitro</Emphasis> cytotoxic activities of 2-alkyl-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-2,6-diazacyclopenta[<Emphasis Type="Italic">b</Emphasis>]anthracene-5,10-diones

A series of 2-alkyl-2,3-dihydro-1H-2,6-diazacyclopenta[b]anthracene-5,10-diones (4a–f) was synthesized and their in vitro cytotoxic activities were evaluated against six human cancer cell lines (HCT15, SK-OV-3, SNB19, A549, MCF7 and MCF7/ADR). They all appeared to be less potent than doxorubicin against all doxorubicin sensitive human cancer cell lines tested. However, these compounds retained considerable cytotoxic activity against the doxorubicin-resistant cell line MCF7/ADR, implying their therapeutic potential to treat doxorubicin-resistant tumors. The most active compound 4c was equipotent with doxorubicin against HCT15 cell line.     

Synthesis of New Nonclassical Acridines,Quinolines, and Quinazolines Derived from Dimedone for Biological Evaluation

New nonclassical acridines, quinolines, and quinazolines were prepared starting from cyclic β‐diketones, namely dimedone, through application of Hantzsch addition, Michael addition, and Mannich reactions, respectively. The antimicrobial activity revealed that decahydroacridin‐1,8‐dione 2e bearing a 3‐nitrophenyl group and hexahydroquinoline 4e having a 2,4‐dichlorophenyl moiety were the most active compounds against both Gram‐positive and ‐negative bacteria based upon using the disc diffusion method. Cytotoxic activity studies for decahydroacridin‐1,8‐diones 2a–e against liver carcinoma cells (HepG₂) using the MTT cell viability assay revealed that decahydroacridin‐1,8‐dione bearing a 4‐methylphenyl moiety 2d showed a higher cytotoxic activity (IC₅₀ = 4.42 µg/mL) than the other derivatives.     

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.     

Design,Synthesis and Molecular Docking Studies of Novel Indole–Pyrimidine Hybrids as Tubulin Polymerization Inhibitors

A series of novel hybrids of indole–pyrimidine‐containing piperazine moiety were designed, synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. The results indicated that most of these compounds possessed significant cytotoxic potency against four cancer cell lines, HT‐29, A549, MDA‐MB‐231 and MCF‐7. Particularly, the most promising compound 34 showed more potent and broad‐spectrum cytotoxic activities with the IC₅₀ values ranged from 5.01 to 14.36 μm against A549, MDA‐MB‐231 and MCF‐7 cell lines. Meanwhile, 34 also displayed the most potent tubulin polymerization inhibitory activity with IC₅₀ value of 11.2 μm . Furthermore, molecular docking analysis demonstrated 34 interacts and binds efficiently with the tubulin protein at the colchicine‐binding site. It was worth noting that the compound did not affect the normal human embryonic kidney cells, HEK‐293. These results suggest that this novel class of indole–pyrimidine hybrids may have potential to be developed as new a class of tubulin polymerization inhibitors.     

Design,synthesis, and in vitro antimicrobial activity of hydrazide–hydrazones of 2‐substituted acetic acid

In this study, 30 hydrazide–hydrazones of phenylacetic ( 3 – 10 ) and hydroxyacetic acid ( 11 – 32 ) were synthesized by the condensation reaction of appropriate 2‐substituted acetic acid hydrazide with different aromatic aldehydes. The obtained compounds were characterized by spectral data and evaluated in vitro for their potential antimicrobial activities against a panel of reference strains of micro‐organisms, including Gram‐positive bacteria, Gram‐negative bacteria, and fungi belonging to the Candida spp. The results from our antimicrobial assays indicated that among synthesized compounds 3 – 32 , especially compounds 6 , 14, and 26 showed high bactericidal activity (MIC = 0.488–7.81 μg/ml) against reference Gram‐positive bacteria, and in some cases, their activity was even better than that of commonly used antibiotics, such as cefuroxime or ampicillin.     

In vitro biological activities of new heterocyclic chalcone derivatives

This work reports the synthesis and characterization of new heterocyclic chalcone derivatives 3(a–j) and in vitro biological evaluation for antiproliferative, antioxidant, antibacterial, antifungal, and antiviral properties. The antiproliferative efficacy and LC₅₀ of the compounds against HepG2 cell lines were determined. The LC₅₀ for 3d was found to be 8 μg/mL. All the compounds exhibited moderate DPPH scavenging activity and moderate to good antimicrobial activity against tested bacterial and fungal strains. Further, the compounds at their respective maximum non-toxic concentrations did not inhibit DNA viruses like buffalopox, camelpox, and goatpox.