New Series Of Benzo Research Articles

Acid‐Mediated One‐Pot Three‐Component Tandem Cyclization: Access to Some New Series of Benzo[5,6]chromeno[2,3‐d]pyrimidine Derivatives

AbstractAn efficient one‐pot synthesis of some new series of benzo[5,6]chromeno[2,3‐d]pyrimidine derivatives is reported by the three‐component condensation reaction of 2,3‐dihydroxynaphthalene, 2‐thiobarbituric acid and aromatic aldehydes using sulfuric acid as the catalyst in glacial acetic acid under reflux condition. This transformation apparently proceeds through Michael addition, intra‐molecular heterocyclization and dehydration sequences. This protocol provides cleaner reaction profiles, good to high yields, operational simplicity, easy workup, readily accessible starting materials and not requires column chromatography for isolation of target products in pure form.

Synthesis, biological profile and computational insights of new derivatives of benzo [B][1,4] diazepines as prospective anticancer agents for inhibiting the CDK-2 protein

In the current work, a new series of benzo[b][1, 4] diazepines (A-1 to C-4) was synthesized and screened against three different human cancer cell lines, HepG2 (hepatocellular carcinoma), HeLa (cervical cancer) and MCF-7 (breast cancer), by employing MTT (MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The outcomes of in vitro screening revealed that all the compounds exhibited momentous anticancer activity, most notably against the MCF-7 cell line by B1–4 compounds. Further, network pharmacology, UALCAN analysis, molecular docking, molecular dynamics (MD) simulations and density functional theory calculations were conducted to explore expression analysis, pharmacokinetics, toxicity profiles and binding interactions of the B1–4 compounds. By UALCAN, we explored the expression analysis of CDK-2 in 19 cancers. Through UALCAN, Pan-cancer analysis revealed that the expression of CDK-2 in 19 cancers was statistically significant. Among the 19 cancers, the CDK-2 expression was significantly upregulated in breast cancer (BRCA), cervical cancer (CESC) and lung carcinoma (LUSC) than normal tissues. Enzyme-docking examination revealed that B1–4 compounds exhibited significant binding affinity against the CDK-2 (PDB ID: 5IEV) drug target protein. Furthermore, MD simulations supported the docking results, which confirmed that the ligand + protein complex was in a stable conformation throughout the simulation time of 100 nanoseconds. Therefore, the present study demonstrates the potential of these benzo [b][1,4] diazepines as promising drug candidates against cancer. Communicated by Ramaswamy H. Sarma

Novel Benzo[4,5]imidazo[1,2-a]pyrimidine derivatives as selective Cyclooxygenase-2 Inhibitors: Design, synthesis, docking studies, and biological evaluation

The present study was aimed at the synthesis and evaluation of a new series of benzo[4,5]imidazo[1,2-a]pyrimidine having a methylsulfonyl group as COX-2 (cyclooxygenase-2) inhibitor pharmacophore. Molecular modeling studies were performed using the Autodock program, and the results demonstrated that methylsulfonyl pharmacophore was adequately placed into the COX-2 active site. The in vitro and in vivo COX-2 inhibitory effects were also evaluated. In the in vitro assay, all newly synthesized compounds showed moderate to good selectivity for the inhibition of the COX-2 enzyme. However, compound 2-(4-(methylsulfonyl) phenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (5a) showed the highest COX-2 inhibitory effect (IC50: 0.05 μM) even more than celecoxib as the reference drug (IC50: 0.06 μM). For the in vivo study, the writing reflex test was used, and the results indicated that all synthesized compounds had well dose-dependent anti-nociceptive activity. The in vivo evaluation also showed that compound 2-(4-(methylsulfonyl)phenyl)-4-(p-tolyl)benzo[4,5]imidazo[1,2-a]pyrimidine (5d) had the highest activity in the writing reflex test (ED50: 5.75 mg/kg). In addition, the cytotoxicity effects of the synthesized compounds were tested on MCF-7 breast cancer cells, and all compounds showed considerable inhibitory results.

Discovery of Novel Benzo[4,5]imidazo[1,2-a]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A2A Adenosine Receptor Antagonists.

The blockade of A2A adenosine receptor (A2AAR) activates immunostimulatory response through regulating signaling in tumor microenvironment. Thus, A2AAR has been proposed as a promising target for cancer immunotherapy. In this work, we designed a new series of benzo[4,5]imidazo[1,2-a]pyrazin-1-amine derivatives bearing an amide substitution at 3-position to obtain potent antitumor antagonist in vivo. The structure-activity relationship studies were performed by molecular modeling and radioactive assay. The in vitro anticancer activities were evaluated by 3',5'-cyclic adenosine monophosphate (cAMP) functional and T cell activation assay. The most potent compound 12o·2HCl showed much higher affinity toward A2AAR (Ki = 0.08 nM) and exhibited more significant in vitro immunostimulatory anticancer activity than clinical antagonist AZD4635. More importantly, 12o·2HCl significantly inhibited the growth of triple-negative breast cancer by reversing immunosuppressive tumor microenvironment in the xenograft mouse model without severe toxicity at the testing dose. These results make 12o·2HCl a promising immunotherapy anticancer drug candidate.

Para toluenesulfonic acid-catalyzed one-pot, three-component synthesis of benzo[5,6]chromeno[3,2-c]quinoline compounds in aqueous medium

Abstract A new series of benzo[5,6]chromeno[3,2-c]quinoline derivatives were successfully synthesized using various arylglyoxal monohydrates, quinoline-2,4-dione, and β-naphthol in H2O:EtOH (2:1) as a green solvent in the presence of catalytic amounts p-toluenesulfonic acid as a mild catalyst under reflux conditions with high yields (83–92%). The reaction conditions were optimized in different solvents at variable thermal conditions, and the optimized reaction condition for this synthesis has been reported. The structures of all new products were defined by 1H-NMR, 13C-NMR, FT-IR, mass spectral data, and HRMS.

Synthesis, molecular modeling and biological evaluation of new benzo[4,5]thieno[3,2-b]pyran derivatives as topoisomerase I-DNA binary complex poisons

A series of new benzo[b]thiophenes 2a-f and benzo[4,5]thieno[3,2-b]pyran derivatives 3a-f and 4a-f were synthesized and their structures were confirmed by elemental analyses and spectral data. All synthesized compounds were evaluated by the National Cancer Institute (NCI, USA) against 60 human tumor cell lines. Compounds 3a-f and 4a-f showed potent cytotoxic effects in one dose assay with mean growth inhibition ranging from 62% to 80%. Six compounds 3a, 3d, 3e, 3f, 4d and 4e were selected by NCI, USA for five dose evaluation against 60 human tumor cell lines. Compounds 3a, 3d, 3e and 3f exhibited very potent and broad spectrum cytotoxicity against almost all cancer cell lines with mean concentration that yield 50% growth inhibition (MG-MID GI50) of 0.1–0.58 µM and mean concentration that produce 100% growth inhibition (MG-MID TGI) of 6.03–10.00 µM. Compounds 4d and 4e exhibited very potent and selective cytotoxic activity against MDA-MB-435 subpanel (melanoma cancer) with GI50 of 0.45 µM and 0.59 µM, respectively. The mechanism of antiproliferative activity was determined for the most active compounds 3a, 3d, 3e, 3f, 4d, and 4evia measuring their half maximal inhibitory concentration (IC50) against topoisomerase I enzyme at different concentrations. Compounds 3a and 3e exhibited excellent activity compared with reference drugs with IC50 of 0.295 µM and 0.219 µM, respectively. Plasmid DNA nicking assay verified that these compounds are topoisomerase I poisons not suppressors. The active compound 3e induced a significant disruption in the cell cycle profile parallel to its effect on apoptosis induction.

A simple and convenient synthesis of novel 9-arylidene-9,11-dihydro-8H-benzo[h]pyrano[3,4 -b]quinolin-8-ones

In this work, a simple and convenient synthesis of a new series of benzo[h]quinoline-based α-arylidene cycloketone derivatives, namely 9-arylidene-9,11-dihydro-8H-benzo[h]pyrano[3,4-b]quinolin-8-ones, has been achieved for the first time in good yields through Claisen–Schmidt condensation reaction of readily synthesized benzo[h]pyrano[3,4-b]quinolin-8-one with aromatic aldehydes under eco-friendly solvent-free condition. Our synthetic strategy features experimental simplicity, inexpensive reagents and satisfactory yields, which would contribute to the usefulness of this method.

Synthesis and biological evaluation of new benzo[d][1,2,3]triazol-1-yl-pyrazole-based dihydro-[1,2,4]triazolo[4,3-a]pyrimidines as potent antidiabetic, anticancer and antioxidant agents

A series of new benzo[d][1,2,3]triazol-1-yl-pyrazole-based dihydro-[1,2,4]triazolo[4,3-a]pyrimidine derivatives 4a-p were synthesized and well characterized by using IR, 1H, 13C NMR and mass spectral data. Finally, the structure of the compound 4l was solved unambiguously by single-crystal X-ray diffraction (SXRD) which confirms all the structures 4a–p. The in vitro α-glucosidase inhibition, anticancer (A549 and MCF-7 cell lines) and antioxidant studies of the title compounds 4a–p were screened. Among all the compounds, 4g, 4h and 4n exhibited significant α-glucosidase inhibition activity with the IC50 values 20.12 ± 0.19 µM, 21.55 ± 0.46 µM and 24.92 ± 0.98 µM. Similarly, the compounds 4h, 4d and 4e showed potent anticancer activity against A549 (human lung carcinoma) cell line with IC50 values 3.64 µM, 4.73 µM and 4.56 µM, respectively, whereas the compounds 4c and 4o displayed potent anticancer activity against human breast cancer (MCF-7) cell line with IC50 values of 2.66 µM and 2.11 µM. In addition, the antioxidant activity revealed that the compounds 4e and 4h exhibited potent antioxidant activity (IC50: 4.25 µM and 5.40 µM). To determine the safety profile of the most active compounds 4c, 4d, 4e, 4g, 4h, 4n and 4o were tested against non-cancer HEK293 cell line (human embryonic kidney 293), results in the lower toxicity of these compounds. New benzo[d][1,2,3]triazol-1-yl-pyrazole-based dihydro-[1,2,4]triazolo[4,3-a]pyrimidines were synthesized. The target compounds were showed significant α-glucosidase inhibition, anticancer and antioxidant activities.

Benzo[d]imidazol-5-yl)-5-(substituted)-1,3,4-Oxadiazoles: Synthesis, Anticancer, Antimicrobial and In Silico Studies

Background:Cancer is a fatal disease for mankind; continuous research is still going on for the invention of potent anticancer drugs. In this view, 1, 3, 4-Oxadiazoles are privileged molecules which attracted medicinal chemists towards their anticancer properties.Methods:A new series of benzo[d]imidazol-5-yl)-5-(substituted)-1,3,4-oxadiazole derivatives was synthesized in an efficient ‘one-pot’ nitro reductive cyclization using sodium dithionite as a cyclizing agent by a conventional method with good yield. All the structures of the synthesized molecules were characterized by IR, 1H NMR, HRMS and Mass spectral analysis. Anticancer activity screening against A375 melanoma cancer cell line and MDA-MB-231 breast cancer cell line along with antimicrobial activity were carried out using agar well diffusion method.Results:Compounds 8a and 8j of the series emerged as potent anticancer agents against A375 melanoma cancer cell line with IC50 47.06 µM and 36.76 µM, respectively. In silico studies also revealed that compounds 8a and 8j showed highest interaction with 2OH4 protein of VEGFR-2 tyrosine kinase. Substantial antibacterial and antifungal activities against the tested microorganism were observed for compounds 8j and 8g.Conclusion:Potent anticancer property has been observed with 1,3,4-Oxadiazole linked tetrafluro substituted benzene ring 8j indicating that future research on these type of molecules can be continued to improve the anticancer activity.

Synthesis of a new series of benzo[d]imidazo[2,1-b]thiazole-1-ium hydroxides by a one-pot, three-component reaction in water

Herein, we report the green synthesis of a new series of benzo[d]imidazo[2,1-b]thiazole-1-ium hydroxide derivatives by a one-pot, three-component reaction of arylglyoxals, quinoline-2,4-diol, and 2-aminobenzothiazole in the presence of TEA/AcOH (1:2) as a catalyst at 50 °C in water, which appears as a green solvent. The structures of all 12 examples were confirmed by 1H NMR, 13C NMR, mass spectral data, and FT-IR. This procedure provides mild reaction conditions, using green solvent, high yields, easy work-up and simple isolation of structurally divers tricyclic benzo[d]imidazo[2,1-b]thiazole derivatives which may have biological and pharmaceutical activities.

Design, synthesis and biological evaluation of novel benzo- and tetrahydrobenzo-[h]quinoline derivatives as potential DNA-intercalating antitumor agents

A new series of benzo- and tetrahydro benzo-[h]quinoline bearing a flexible (dimethylamino)ethylcarboxamide side chain was designed and synthesized as DNA-intercalating antitumor agents. The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including MCF-7, A2780, C26 and A549. In general, saturated quinolines (tetrahydrobenzo[h]quinolines) exhibited more cytotoxicity compared to their corresponding unsaturated quinolines (benzo[h]quinolines). Compound 6e showed significant cytotoxicity against all four human cancer cell lines with IC50 values ranging from 1.86 to 3.91 μM. The interaction of the selected compounds showed significant cytotoxicity (6b, 6e, 6i and 6j) with calf thymus DNA (CT-DNA) was studied by UV and florescent spectroscopy. In general, benzo[h]quinolines showed higher interacting effect with DNA than their corresponding saturated tetrahydrobenzo[h]quinolines. Compound 6i exhibited the most DNA intercalating effects among the series. The apoptotic induction potential of the most cytotoxic compounds (6e, 6b and 6i) in A549 cells was studied using Annexin V-FITC/Propidium iodide staining assay. Compound 6e which showed the most cytotoxic effect against A549 cancer cells also exhibited stronger apoptotic induction activity in comparison with 6b and 6i.The docking was performed in order to study the DNA interaction properties of these compounds. According to the computational data, these compounds can interact with DNA as DNA-intercalating agents.

Synthesis, Conversions, and Anti-Monoamine-Oxidase and Anticonvulsant Activity of Ethyl 4′-Amino-5′,8′-Dimethyl-1′H-Spiro[Cyclohexane-1,2′-Naphthalene]-3′-Carboxylate

7,10-Dimethyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexane]-4(6H)-one was synthesized from ethyl 4′-amino-5′,8′-dimethyl-1′H-spiro[cyclohexane-1,2′-naphthalene]-3′-carboxylate and reacted with various alkyl(benzyl)halides to afford a new series of benzo[h]quinazolines containing methyl substituents on the benzene ring. The anti-monoamine-oxidase and anticonvulsant activities of the benzo[h]quinazolines were studied.

Synthesis, SAR and molecular docking studies of benzo[d]thiazole-hydrazones as potential antibacterial and antifungal agents

A series of new benzo[d]thiazole-hydrazones analogues were synthesized and screened for their in vitro antibacterial and antifungal activities. The results revealed that compounds 13, 14, 15, 19, 20, 28 and 30 exhibited superior antibacterial potency compared to the reference drug chloramphenicol and rifampicin. Compounds 5, 9, 10, 11, 12, 28 and 30 were found to be good antifungal activity compared to the standard drug ketoconazole.A preliminary study of the structure-activity relationship (SAR) revealed that the antimicrobial activity depended on the effect of different substituents on the phenyl ring. The electron donating (OH and OCH3) groups presented in the analogues, increase the antibacterial activity (except compound 12), interestingly, while the electron withdrawing (Cl, NO2, F and Br) groups increase the antifungal activity (except compound 19 and 20). In addition, analogues containing thiophene (28) and indole (30) showed good antimicrobial activities. Whereas, aliphatic analogues (24–26) shown no activities in both bacterial and fungal stains even in high concentrations (100µg/mL). Molecular docking studies were performed for all the synthesized compounds of which compounds 11, 19 and 20 showed the highest glide G-score.

Synthesis and Spectroscopic Characterization of a New Series of Benzo[E][1,3]Oxazepine Compounds from Schiff Bases

The present work includes synthesis, characterization and investigation the biological activity of a new series of benzo [e][1, 3]oxazepine compounds which were prepared from Schiff bases. The synthetic routes have been divided into two steps as follows: The first step includes the synthesis of Schiff bases, by treatment of 4-amino diphenyl amine and different substituted benzaldehydes in absolute ethanol using glacial acetic acid as catalyst. The second step of this work is the synthesis of a series benzo [e][1, 3] oxazepine, by the reaction of the synthesized Schiff bases with phthalic anhydride in dry benzene. The structures of the synthesized products were confirmed on the basis of (UV-Visible, FT-IR, 1H-NMR, 13C-NMR spectroscopy. Some of the synthesized compounds were evaluated for antibacterial activity, against two types of bacteria, Staphylococcus aureus (Gram positive) and Pseudomonas aeruginosa (Gram negative).The results showed the high sensitivity of the synthesized compounds to both types of bacteria.

Synthesis and transformations of 3-allyl-7,10-dimethyl-2-sulfanylidene-2,3,5,6-tetrahydrospiro[benzo[h]quinazoline-5,1′-cyclopentan]-4(1H)-one

Ethyl 4′-amino-5′,8′-dimethyl-1′H-spiro[cyclopentane-1,2′-naphthalene]-3′-carboxylate reacted with allyl isothiocyanate to give 3-allyl-7,10-dimethyl-2-sulfanylidene-2,3,5,6-tetrahydrospiro[benzo[h]quinazoline- 5,1′-cyclopentan]-4(1H)-one. Reactions of the latter with alkyl halides and hydrazine hydrate and subsequent transformations of the products afforded a series of new benzo[h]quinazoline derivatives containing an allyl group in the 3-position.

Synthesis of benzo[d]thiazole-hydrazone analogues: molecular docking and SAR studies of potential H+/K+ ATPase inhibitors and anti-inflammatory agents.

A series of new benzo[d]thiazole-hydrazones were synthesized and characterized by analytical and spectroscopic techniques. All the compounds were screened for their in vitro inhibition of H+/K+ ATPase and anti-inflammatory effects. The results revealed that compounds 6-8, 13-15, 18-20, 22, 23 and 27-30 displayed excellent inhibitory activity against H+/K+ ATPase, and their IC50 values were lower than those of the standard compound omeprazole. Compounds 2-5, 9-12, 28 and 30 exhibited better anti-inflammatory activity in comparison to the standard compound indomethacin. Studies of the structure-activity relationship (SAR) showed that electron-donating groups (OH and OCH3) favored inhibitory activity against H+/K+ ATPase, whereas electron-withdrawing groups (F, Cl, Br and NO2) favored anti-inflammatory activity, and derivatives with both electron-donating (OH and OCH3) and electron-withdrawing (Br) groups (16-18) displayed reasonable activity, whereas aliphatic analogues (24-26) exhibited less activity and heterocyclic analogues (27-30) displayed moderate activity in both biological studies. Molecular docking studies were performed for all the synthesized compounds, among which compounds 19 and 20 exhibited the highest docking scores for inhibitory activity against H+/K+ ATPase, whereas compounds 10 and 12 displayed the highest docking scores for anti-inflammatory activity.

Design, synthesis, structural elucidation and antimicrobial screening of novel 1, 5-benzothiazepine derivatives derived from thieno [3, 2-d] pyrimidine nucleus

1, 5-Benzo Thiazepine is the Main Seven membered Heterocyclic ring systems reported for their cardiac and Psychotherapeutic activities.1, 5 Benzo Thiazepines were highlighted as important Biologically active Scaffolds. In This Article New series of benzo [b] [1, 5]-thiazepine derivatives 6 a-j were synthesized by applying the cyclo condensation of (E)-3-(thieno [3, 2-d] pyrimidin-6-yl)-1-p-Substituted prop-2-en-1-one derivatives 4a-j with 2amino thio phenol (5) in DMF. The new intermediate Chalcone derivatives 4a-j were obtained from interaction of various P-substituted Acetophenone & Heterocyclic Acetyl derivatives 3(a-j) and thieno[3, 2-d]pyrimidine-7carbaldehyde. The synthesized 1, 5-benzothiazepines 6a-j have been screened for their antimicrobial activity. From anti-bacterial and anti-fungal activity screening results, it has been observed that compounds 6h, 6e, 6i and 6d possess good activity.

Alkyl- and aryl-substituted benzo[ghi]perylenetriimides: Synthesis, characterization and comparison of electrochemical and spectroscopic properties

Benzo[ghi]peryleneimides constitute a unique class of fluorescent perylene dyes which possesses great synthetic diversity due to the presence of a large number of reactive active sites (availability of third imide region). Taking advantage of this additional active site we synthesized a new series of benzo[ghi]perylenetriimides comprised of alkyl- and aryl-substituents in the third imide region. The core extension of perylene diimides was performed using a Diels-Alder reaction to afford diimido anhydride (3) which provided access to the various triimides with yields ranging from 58% to 69%. The combined spectroscopic and electrochemical studies revealed strong electron accepting properties of the triimides. Potential application of the synthesized triimides for various optoelectronic devices and as non-fullerene electron acceptors in photovoltaics is evident from this study.

Synthesis, photophysical characterisation and photostability studies of NIR probes with aliphatic, aromatic and chlorinated terminals in 5- and 9-amino positions of benzo[a]phenoxazines

A new series of benzo[a]phenoxazinium chlorides possessing mono and disubstituted amines with 3-chloropropyl groups at the 9-position, isopropyl, cyclohexyl and phenyl groups as terminals at 5-postion was synthesised. Photophysical studies were performed in dry ethanol and aqueous solutions. The terminals at the 5-amino position were found to influence the acid-base equilibrium. The presence of hydroxyl functionality at 2-position was found to introduce an additional basic form that is the one in equilibrium with the cationic acid form in dry ethanol solutions. The photostability of these compounds in different media was also investigated and a high resistance to photobleaching in model biological membranes was observed. In proteins a moderate of 20% photobleaching occurs in 1 h 30 min, while in water more than 60% of the compound molecules are photodegraded during the same time interval.

Highly Soluble Benzo[ghi]perylenetriimide Derivatives: Stable and Air-Insensitive Electron Acceptors for Artificial Photosynthesis.

A series of new benzo[ghi]perylenetriimide (BPTI) derivatives has been synthesized and characterized. These remarkably soluble BPTI derivatives show strong optical absorption in the range of λ=300–500 nm and have a high triplet-state energy of 1.67 eV. A cyanophenyl substituent renders BPTI such a strong electron acceptor (Ered=−0.11 V vs. the normal hydrogen electrode) that electron-trapping reactions with O2 and H2O do not occur. The BPTI radical anion on a fluorine-doped tin oxide|TiO2 electrode is persistent up to tens of seconds (t1/2=39 s) in air-saturated buffer solution. As a result of favorable packing, theoretical electron mobilities (10−2∼10−1 cm2 V−1 s−1) are high and similar to the experimental values observed for perylene diimide and C60 derivatives. Our studies show the potential of the cyanophenyl-modified BPTI compounds as electron acceptors in devices for artificial photosynthesis in water splitting that are also very promising nonfullerene electron-transport materials for organic solar cells.