Synthesis of Novel Diverse Methoxybenzenes‐substituted 2H/4H‐chromene Derivatives in the Presence of InBr3 (5 mol%) and their Cytotoxic Activity

A series of novel 2‐(trifluoromethyl)‐2H /4H ‐chromene‐3‐carboxylate isomers 3 and 4 functionalized with diverse methoxybenzenes 2 at position 4 in compound 3 and position 2 in compound 4 were prepared in different proportions by nucleophilic substitution on ethyl 2‐hydroxy‐2‐(trifluoromethyl)‐2H ‐chromene‐3‐carboxylate 1 in single step promoted by Indium (III) bromide (5 mol%) a Lewis acid. Regiospecific isomers 3k , 3l , 3m , and 3n prepared by using sterically bulk 1,3,5‐trimethoxy benzene substrate 2e in this reaction. Further, isomers 3a and 4a independently on reaction with amines, only compound 3a could give Michael addition products 5a–c . All the compounds 3a–n , 4a–j , and 5a–c were screened for cytotoxic activity against four human cancer cell lines and found to show high activity at micromolar concentration. The compounds 4h and 5a–c showed promising cytotoxic activity against the tested cancer cell lines. Further, these compounds 4h and 5a–c were docked with protein (1SA0) on colchicine‐binding site of β tubulin suggesting that tubulin inhibition could be the possible mechanism of action for these compounds.     

Synthesis,anti‐proliferative activity,SAR, and kinase inhibition studies of thiazol‐2‐yl‐ substituted sulfonamide derivatives

A series of novel thiazol‐2‐yl substituted‐1‐sulfonamide derivatives were synthesized from anilines. This involved the coupling of sulfonyl chlorides with thiazol amine to obtain the final compounds 7a – 7j and 8a – 8j . All synthesized compounds were screened for anticancer activity against MCF‐7, HeLa, A‐549, and Du‐145 cancer cell lines by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Preliminary bioassay suggests that most of the compounds show anti‐proliferation to different degrees, with doxorubicin used as positive control. The synthesized compounds show IC₅₀ values in the range 2.74–8.17 μM in the different cell lines. The compounds 7d , 7e , 8a , 8d , and 8e were active compared to doxorubicin. The compounds having butyl and pantyl chains were more active than their lower and higher carbon chains and also their ring counterparts.     

Synthesis and Cytotoxic Activity of Some Novel Dihyrobenzo[h]pyrano[3,2‐c]chromene Derivatives

Three‐component reaction of 4‐hydroxy‐2H‐benzo[h]chromen‐2‐one, aromatic aldehydes, and malononitrile in the presence of 1,4‐diazabicyclo[2.2.2]octane (DABCO) in ethanol at room temperature affords good yields of novel dihyrobenzo[h]pyrano[3,2‐c]chromene derivatives. The synthesized compounds examined by MTT assays for cytotoxic activity in two human cancer cell lines (MOLT‐4, HL‐60). Most of the evaluated compounds showed low inhibitory activity against tumor cell line at micromolar concentrations.     

Synthesis and antitumor activity evaluation of some schiff bases derived from 2‐aminothiazole derivatives

A novel series of thiazolyl Schiff bases have been designed and synthesized. These new compounds were obtained by the reactions of 4‐phenyl‐5‐(1H‐1,2,4‐triazol‐1‐yl) thiazol‐2‐amine and substituted aromatic aldehydes and were characterized on the basis of ¹H NMR and elemental analysis. The newly synthesized compounds were screened for their antitumor activity against human cancer cell lines, namely HL‐60 (leukemia), BGC‐823 (stomach), and HEP‐2 (larynx cancer). © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:55–59, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20256     

Efficient Synthesis of Some New 1,3,4‐Thiadiazoles and 1,2,4‐Triazoles Linked to Pyrazolylcoumarin Ring System as Potent 5α‐Reductase Inhibitors

The current study in this article concerned with construction of five‐membered heterocycles with multiple heteroatoms as nitrogen and sulfur from readily available starting materials and reagents. Treatment of 1‐(2‐oxo‐2H‐chromene‐3‐carbonyl)‐3‐phenyl‐1H‐pyrazol‐5(4H)‐one with each of phenylisothiocyanate in alcoholic potassium hydroxide and carbon disulfide in basic medium gave rise to a thioanilide and methylthio derivatives, respectively. Treatment of the latter compounds with a variety of hydrazonoyl halides resulted in construction of thiadiazole moiety linked to pyrazole ring. Furthermore, triazole derivatives were synthesized from the thioanilide derivative through its reaction with methyl iodide followed by reaction with hydrazonoyl halides. 5α‐Reductase inhibition activity for the prepared compounds was investigated against the reference drug anastrozole, and the results showed that the inhibition activity of compounds 5g and 11g is more potent than anastrozole. Also compounds bearing triazole moiety is more potent than compounds bearing thiadiazole one. Moreover, the anti‐prostate cancer screening anti‐androgenic bioassay in human prostate cancer cells for the tested compounds was evaluated, and the results showed great inhibition growth and potential antiandrogens.     

Synthesis and Pharmacological Evaluation of Some New Chromeno[3,4‐c]pyrrole‐3,4‐dione‐based N‐Heterocycles as Antimicrobial Agents

The reaction of 2‐oxo‐2H‐chromene‐3‐carboxamide ( 1 ) with carbon disulfide afforded 1‐mercaptopyrrolo[3,4‐c ]chromene‐3,4‐dione ( 3 ). The latter compound was utilized as versatile building block for new azole systems via incorporating in a series of manipulations including cyclocondensation reactions. The structure of the newly synthesized compounds has been confirmed by IR, ¹H NMR, ¹³C NMR, mass spectral, and elemental analysis. Furthermore, some selected compounds were screened in vitro for their antimicrobial activities. The results declared that most of the synthesized compounds have high antimicrobial activity.     

Palladium Catalyzed Tricyclohexylphosphine Ligand Associated Synthesis of N‐(2‐(pyridine‐4‐yl)‐1H‐pyrrolo[3,2‐c]‐pyridin‐6‐yl‐(substituted)‐sulfonamide Derivatives as Antiproliferative Agents

A series of novel N‐(2‐(pyridine‐4‐yl)‐1H‐pyrrolo[3,2‐c]‐pyridin‐6‐yl‐(substituted)‐sulfonamide derivatives were synthesized from 2‐bromo‐6‐nitro‐1H‐pyrrolo[3,2‐c]pyridine through a series of reactions including Suzuki reaction, reduction, protection, and sulfonamide coupling. All the synthesized compounds were screened for anticancer activity against MCF‐7, HeLa, A‐549, and Du‐145 cancer cell lines by the MTT assay. The preliminary bioassay suggests that most of the compounds show antiproliferation with different degrees. Doxorubicin was used as a positive control. Among the synthesized compounds, 8d and 8h were most active compared with the standard in cell line data. The synthesized compounds 8d and 8h show IC₅₀ values in the range of 1.88–5.16 μM for all the cell lines. Compounds 8d and 8h were further studied for a panel of eight human kinase at 10 μM concentrations and the result shows 64% to 70% inhibitions for both Aurora‐A and Aurora‐B kinase.     

Synthesis and Anti‐tumor Evaluation of B‐ring Modified Caged Xanthone Analogues of Gambogic Acid

Gambogic acid (GA, 1 ), the most prominent member of Garcinia natural products, has been reported to be a promising anti‐tumor agent. Previous studies have suggested that the planar B ring and the unique 4‐oxa‐tricyclo[4.3.1.0^3,7]dec‐2‐one caged motif were essential for anti‐tumor activity. To further explore the structure‐activity relationship (SAR) of caged Garcinia xanthones, two new series of B‐ring modified caged GA analogues 13a – 13e and 15a – 15e were synthesized utilizing a Claisen/Diel‐Alder cascade reaction. Subsequently, these compounds were evaluated for their in vitro anti‐tumor activities against A549, MCF‐7, SMMC‐7721 and BGC‐823 cancer cell lines by MTT assay. Among them, 13b – 13e exhibited micromolar inhibition against several cancer cell lines, being approximately 2–4 fold less potent in comparison to GA. SAR analysis revealed that the peripheral gem‐dimethyl groups are essential for maintaining anti‐tumor activity and substituent group on C1 position of B‐ring has a significant effect on potency, while modifications at C‐2, C‐3 and C‐4 positions are relatively tolerated. These findings will enhance our understanding of the SAR of Garcinia xanthones and lead to the development of simplified analogues as potential anti‐tumor agents.     

Moxifloxacin/Gatifloxacin‐1,2,3‐triazole‐isatin Hybrids with Hydrogen‐Bond Donor and Their In Vitro Anticancer Activity

A series of novel moxifloxacin/gatifloxacin‐1,2,3‐triazole‐isatin hybrids ( 8a – i ) were designed, synthesized, and screened for their in vitro anticancer activity in this paper. All of the synthesized hybrids were active against A549 and HepG2 cancer cell lines, whereas the parent drugs moxifloxacin and gatifloxacin were devoid of activity. Among them, hybrid 8i (IC₅₀: 41.1–98.3 μM) showed considerable activity against A549, HepG2, and MCF‐7 cancer cell lines, and it was no inferior to Vorinostat (IC₅₀: 64.32 to >100 μM) against the three cancer cell lines. Thus, this kind of hybrids has potentiality for discovery of new anticancer candidates for clinical deployment in the control and eradication of cancers.     

Synthesis and Pharmacological Evaluation of 4‐Aryloxyquinazoline Derivatives as Potential Cytotoxic Agents

In the present study, novel 4‐aryloxyquinazoline derivatives were synthesized and screened for in vitro cytotoxicity on human cancer cell lines at 10 μM. Some of the synthesized compounds displayed moderate to significant and selective cytotoxic activity against various leukemia, melanoma, ovarian, breast, and colon cancer cell lines. (E)‐3‐(3,4‐Dimethoxyphenyl)‐1‐(4‐(quinazolin‐4‐yloxy)phenyl)prop‐2‐en‐1‐one ( 9b ) was the most potent compound among all with an average growth inhibition of 70% against leukemia cancer cell lines. The compound also produced strong inhibition (75%) of colon cancer cell lines with 42.58% lethality of HCT‐116 cell line.     

Synthesis of Bis‐acridine Derivatives Exhibiting Anticancer and Anti‐inflammatory Activity

A series of bis‐acridine derivatives 3a – j and 5a – j have been synthesized by condensation of 9‐chloro‐2,4‐(un)substituted acridines (1a – e) and 9‐isothiocyanato‐2,4‐(un)substituted acridines (4a – e) with diamine 2a and 2b , respectively. These bis‐acridines were evaluated in vitro for activity against a panel of human cancer cell lines of lung (NCI H‐522), ovary (PA1), breast (T47D), colon (HCT‐15), and liver (HepG2). Several bis‐acridines were found to possess good anticancer activity against various cancer cell lines. Of these, compound 3h exhibited good anticancer activity against all cancer cell lines tested except liver (HepG2) cell line. In addition to this, these compounds were screened for anti‐inflammatory activity at a dose of 50 mg/kg p.o. Compound 3g exhibited 41% anti‐inflammatory activity, which is better than most commonly used standard drug ibuprofen, which showed 39% anti‐inflammatory (at 50 mg/kg p. o.) activity.     

Design,synthesis of (Z)‐3‐benzyl‐5‐((1‐phenyl‐3‐(3‐((1‐ substituted phenyl‐1H‐1,2,3‐triazol‐4‐yl)methoxy)phenyl)‐1H‐pyrazol‐4‐yl)methylene)thiazolidine‐2,4‐dione analogues as potential cytotoxic agents

In an attempt to achieve promising cytotoxic agents, a series of new (Z)‐3‐benzyl‐5‐((1‐phenyl‐3‐(3‐((1‐substituted phenyl‐1H‐1,2,3‐triazol‐4‐yl)methoxy)phenyl)‐1H‐pyrazol‐4‐yl)methylene)thiazolidine‐2,4‐diones 10 a‐n were designed, synthesized, and characterized by ¹H NMR, ¹³C NMR, IR, and ESI‐MS techniques. These compounds synthesized from appropriate reaction procedures with better yields. All the novel synthesized compounds 10a‐n were evaluated for their cytotoxic activity against the MCF‐7 cell line (Human breast cancer cell line) at different concentrations of 0.625, 1.25, 2.5, 5, and 10 μM, respectively. The cytotoxic evaluation assay is presented in terms of IC₅₀ values and percentage cell viability reduction compared against standard drug cisplatin. Among all novel synthesized compounds 10a‐n , some of the representative analogues particularly 10g and 10e exhibit remarkable cytotoxic activity with IC₅₀ values 0.454 and 0.586 μM, comparable to that of the standard drug cisplatin, and some analogues 10d , 10f , 10k, and 10m also have shown significant activity.     

Total Synthesis of Indole‐Derived Allocolchicine Analogues Exhibiting Strong Apoptosis‐Inducing Activity

A series of novel pyrrolo‐allocolchicine derivatives (containing a 1‐methyl‐1H‐indol‐5‐yl moiety replacing ring C) was synthesized. The tetracyclic ring system was constructed by Suzuki–Miyaura cross‐coupling of a 1‐methylindole‐5‐boronate with an ortho‐iodo‐dihydrocinnamic acid derivative and subsequent intramolecular Friedel–Crafts acylation. After reduction of the resulting ketone, the nitrogen functionality was introduced in a Mitsunobu‐type reaction by using zinc azide followed by LiAlH₄ reduction. Structural assignments were supported by X‐ray crystallography. The compounds synthesized were then tested against BJAB tumor cells and found to exhibit pronounced cytotoxic activity (proliferation inhibition and apoptosis induction). The ketone 24 b was even active at sub‐nanomolar concentration. In addition, the antitumor potential of the compounds was confirmed by using B lymphoid cell lines.     

Design,Synthesis, and Evaluation of the Anticancer Properties of a Novel Series of α‐(Benzoylamino)‐β‐substituted Acrylic Amide Derivatives of Pyrazolo[1,5‐a]pyrimidine

A novel series of α‐(benzoylamino)‐β‐substituted acrylic amide derivatives of pyrazolo[1,5‐a]pyrimidine has been synthesized using a convergent multistep synthesis. The synthesized compounds were characterized by ¹H NMR, ¹³C NMR, ESI‐MS, and IR analyses. Those new compounds were screened for their in vitro antiproliferative activity using an MTT assay analysis. Out of nine derivatives synthesized in the current study, compounds 13g , 13d , 13h , and 13i exhibited the greatest anticancer activities in HeLa and HepG₂ cell lines. The in vitro anticancer activity of compound 13g against HeLa, HepG₂, and MCF‐7 cell lines is superior to the marketed drugs paclitaxel and SAHA.     

Synthesis and Anti‐tumor Evaluation of Novel C‐37 Modified Derivatives of Gambogic Acid

Gambogic acid (GA, 1 ), the most prominent representative of Garcinia natural products, has been reported to be a promising anti‐tumor agent. In order to further explore the structure‐activity relationship of GA and discover novel GA derivatives as anti‐tumor agents, 17 novel C‐37 modified derivatives of GA were synthesized and evaluated for their in vitro anti‐tumor activities against A549, HCT‐116, BGC‐823, HepG2 and MCF‐7 cancer cell lines. Among them, 11 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 8 was almost 5–10 folds more active than GA against A549 and BGC‐823 cell lines with the IC₅₀ values of 0.12 µmol·L^?1 and 0.57 µmol·L^?1, respectively. Chemical modification at C‐37 position of GA by introducing of hydrophilic amines could lead to increased activity and improved drug‐like properties. These findings will enhance our understanding of the structure‐activity relationship (SAR) of GA and lead to the discovery of novel GA derivatives as potential anti‐tumor agents.     

Ciprofloxacin/Gatifloxacin‐1,2,3‐triazole‐isatin Hybrids and Their In Vitro Anticancer Activity

Eleven novel ciprofloxacin/gatifloxacin‐1,2,3‐triazole‐isatin hybrids ( 8a – k ) were designed, synthesized, and screened for their in vitro anticancer activity in this paper. A significant part of the synthesized hybrids was active against A549, HepG2, and SF‐268 cancer cell lines, whereas the parent drugs ciprofloxacin and gatifloxacin were devoid of activity. Among them, hybrid 8i (IC₅₀: 78.1–90.7 μM) was found to be the most active against A549, HepG2, and SF‐268 cancer cell lines, and it was comparable with or better than Vorinostat (IC₅₀: 71.1 to >100 μM). Thus, these kind hybrids have potentiality for discovery of new anticancer candidates for clinical deployment in the control and eradication of cancers.     

The Synthesis and Biological Evaluation of N‐Substituted 1H‐Benzimidazol‐2‐yl‐1H‐pyrazole‐3,5‐diamines

The synthesis of 1H‐benzimidazol‐2‐yl‐1H‐pyrazole‐3,5‐diamines has been developed. Synthesized bisheteroaryls contain two privileged medicinal scaffolds, aminopyrazole and benzimidazole, with two diversity positions at N1 of benzimidazole and C3 of pyrazole, respectively. The three‐step synthesis includes the Mitsunobu N‐alkylation of benzimidazole and subsequent one‐pot formation of aminopyrazole involving substitution of methylthio groups with amine and hydrazine followed with final ring closure. Inhibitory activity toward cyclin‐dependent kinase 2/cyclin E and cytotoxicity against two cancer cell lines were evaluated for all novel pyrazoles. Two compounds showed modest cyclin‐dependent kinase inhibition activity and cytotoxicity against cancer cell lines K562 and MCF7.     

Synthesis and In Vitro Anticancer Evaluation of Symmetrically Bridged 1,3‐thiazine Derivatives

A series of bis‐1,3‐thiazine derivatives 3a–o were synthesized from the condensation reactions of symmetric dialdehydes 1a–c possessing aliphatic ether spacer units with 3‐substituted‐amino‐2‐cyano‐3‐mercaptoacrylamides 2a–e . The chemical structures of the products were fully characterized by using different spectroscopic techniques, such as ¹H NMR, ¹³C NMR, IR, electron impact mass spectrometry, and elemental analysis. Compounds 3a , 3f , and 3k underwent ring opening followed by recyclization and alkylation in basic medium to afford bis‐pyrimidinones 4a–c and 5a–c . The anticancer potential of the new bis‐1,3‐thiazines was assessed in vitro against six different human cell lines, including lung A549, colon HCT116, breast MCF‐7, prostate PC3, liver HepG2, and normal melanocyte HFB4. The results revealed a potent activity of compounds 3e and 3k against breast and liver cancer cell lines in comparison with the reference drug doxorubicin with no noticeable toxicity on normal cells.     

Synthesis and Bioactivity of Novel N,N′‐Diacylhydrazine Derivatives Containing Furan (III)

42 novel diacylhydrazine derivatives containing furan were synthesized by the reaction of 5‐substituted phenyl‐2‐furoyl chloride with substituted benzohydrazide in anhydrous dichloromethane under reflux. Their structures were confirmed by IR, ¹H NMR, MS and elemental analysis. Insecticidal and antitumor activity of these new compounds was evaluated. The preliminary bioassays showed that the target compounds exhibited larvicidal activity to the Mythimna separate, some of them exhibited good or moderate larvicidal activity. At the concentration of 0.1%, compounds I2 , I4 , I5 , and III1 showed 95.0%, 90.0%, 95.0% and 95.0% larvicidal activity to Mythimna separate respectively. Some compounds such as I2 , I4 , I5 and III1 showed the typical IGRs' activity, which could induce the larvae premature, abnormal, and lethal larval molt. Results of anticancer activity indicated that some compounds exhibited potential activity against some human cancer cell lines, for example, I1 and IV showed good activity to the BGC‐823 and the inhibitory rates were 60.86% and 61.94% respectively at 10 µmol/L.     

Facile Synthesis of Novel 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one Derivatives as Potential Anticancer Agents

A series of 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 6a – l ) derivatives has been efficiently synthesized by straightforward sequential reactions. Tandem Vilsmeier Hack reaction/cyclization/bromination/Suzuki cross‐coupling reactions were successfully applied to the preparation of title compounds in good‐to‐high yields. In the synthetic sequences, 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehydes ( 2 ) were found to react with ammonium thiocyanate to yield the corresponding 3‐(isothiazol‐5‐yl)‐2H‐chromen‐2‐ones ( 3 ). These derivatives were brominated with N‐bromo succinamide to yield the corresponding regioselective 3‐(4‐bromoisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 4 ). Finally, compound 4 was treated with various phenyl/pyrazole/7H –pyrrolo[2,3‐d]pyrimidinyl boronic acids 5a – l in the presence of K₂CO₃ and Pd catalyst in dimethylformamide to yield the corresponding title derivatives 6a – l . All the synthesized compounds were characterized by analytical and spectral studies. All the final compounds were screened against different cancer cell lines (A549, PC3, SKOV3, and B16F10), and among these compounds, 6b , 6g , 6h , and 6l displayed moderate cytotoxic activity against the tested cell lines.