Synthesis and cytotoxicity of novel 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N-phenethylbenzenesulfonamides

A new series of 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N-phenethylbenzenesulfonamide derivatives 5 were synthesized through the Click approach and evaluated for their cytotoxic activity against four cancer cell lines (HuCCA-1, HepG2, A549, and MOLT-3). Most of the synthesized triazoles 5 displayed cytotoxicity against MOLT-3 cell line, except for analogs 5a–c and 5e. Significantly, 4-phenyltriazoles (5a and 5n), 4-(naphthalen-2-yloxy)methyltriazole 5d, as well as 4-((2-oxo-2H-chromen-7-yl)oxy)methyltriazole 5l showed higher cytotoxic activity against HepG2 cells than the reference drug, etoposide. Interestingly, the 4-phenyltriazole 5a was the most potent and promising compound with IC₅₀ value of 9.07 μM against HepG2 cell line. The analog 5a also exerted the highest cytotoxic activity against HuCCA-1 cells. This finding provides the novel lead molecules for further development.     

Synthesis and cytotoxicity of novel N-sulfonyl-1,2,3,4-tetrahydroisoquinoline thiosemicarbazone derivatives

The modified Pictet–Spengler reaction of phenylethylbenzene sulfonamide with a commercially available glyoxal to construct 1-benzoyl- and 1-acetyl-1,2,3,4-tetrahydroisoquinolines 9a–n has been reported. The reaction could be accomplished, regardless of the oxygenation pattern on the aromatic ring, leading to the N-sulfonyltetrahydroisoquinoline analogs which are versatile intermediates for the synthesis of new thiosemicarbazone analogs of 1,2,3,4-tetrahydroisoquinoline. Bioactivity test revealed that most thiosemicarbazones displayed cytotoxic potency against MOLT-3 cell lines with an IC₅₀ less than 20 μg/mL. Significantly, the thiosemicarbazone analog of 1-acetyltetrahydroisoquinoline 9j was the most potent cytotoxic compound against HuCCA-1, HepG2, and MOLT-3 cells. This study provides the novel lead molecules for further development.     

Cytotoxicity and QSAR study of (thio)ureas derived from phenylalkylamines and pyridylalkylamines

Simplified 1,3-disubstituted urea derivatives (11–24) of phenylethylamines, homoveratylamines, 2-pyridylethylamines, 2-picolylamines as well as xylylenediamines were synthesized and investigated for their cytotoxic activities. The results revealed that most analogs displayed cytotoxicity against HepG2 and MOLT-3 cell lines. The bis-thiourea derivatives 23 and 24 exhibited higher inhibitory potency against HepG2 cell than the reference drug, etoposide. 1,1′-(1,3-phenylenebis(methylene))bis(3-(4-chlorophenyl)thiourea) 24 was shown to be the most potent cytotoxic compound against MOLT-3 cell line with an IC₅₀ value of 1.62 μM. QSAR studies suggested that compounds with high ionization potential displayed high cytotoxicity against HuCCA-1 cell line. Furthermore, derivatives with dimethoxyphenyl group had high radial distribution function with a correspondingly high cytotoxicity against A549 cell line. Moreover, analogs 23 and 24 had low values of E _HOMO (energy of the highest occupied molecular orbital energy) as well as high cytotoxicity against HepG2 cell line. This study affords an easily accessible approach for the synthesis of promising anticancer agents. The developed QSAR models provided pertinent information into the physicochemical properties governing the investigated biologic properties.     

Synthesis and antitumor activity evaluation of 2-arylisoquinoline-1,3(2H,4H)-diones in vitro and in vivo

Six 2-(2-acylaminobenzothiazol-6-yl)isoquinoline-1,3(2H,4H)-diones (1a–1f) and five 2-arylisoquinoline-1,3(2H,4H)-diones (1g–1k) were synthesized by refluxing homophthalic anhydrides with 2-acylaminobenzothiazolyl-6-amine or substituted aniline in glacial acetic acid. The cytotoxic activities of 1a–1k were evaluated via MTT method against A431, A549, and PC3. Compound 1b relatively displayed a higher cytotoxic activity than the others. The antitumor effect of 1b were evaluated in established nude mice PANC-1 xenograft model. The results suggest that compound 1b could potentially inhibit tumor growth.     

Synthesis and cytotoxic activity of diaryl urea derivatives with a 4-methylpiperazinylcarbonyl moiety

Eleven diarylurea derivatives (1a–1k) bearing N-methylpiperazinyl moiety were synthesized by the reaction of isocyanate with arylamine. The structures of 1a–1k were characterized by ¹H-NMR and MS. The cytotoxic activities of 1a–1k were evaluated via MTT method against human lung adenocarcinoma epithelial cell line A549 and human prostate carcinoma cell line PC3. Compounds 1d and 1k displayed potent cytotoxic activity. The results suggested that the activities are considerably related to the substituent group at another phenyl ring.     

Synthesis, cytotoxicity, and structure–activity insight of NH- and N-methyl-3,5-bis-(arylidenyl)-4-piperidones

Twenty-one NH- and N-methyl-3,5-bis-(arylidenyl)-4-piperidone analogs of curcumin, 12 of which are novel, were synthesized and evaluated for their cytotoxicity against B16 (murine melanoma) and L1210 (murine lymphoma) cells grown in culture. These curcumin analogs are related to a known anticancer STAT3 inhibitor 3,5-bis-(4-fluorobenzyl)-4-piperidone (3). The compounds showed remarkable cytotoxicity, especially against B16 cells. The dimethoxy substituted analogs 4e and 4f and dihydroxy analog 4i emerged as the most active compounds with IC₅₀ values in the range of 0.2–2.3 μM. 4e, f, and i were about 10-times more cytotoxic against both cell lines than 3. Analysis of the results demonstrates that the position of the hydroxyl group is crucial for cytotoxicity. Amino-containing analogs are generally less active than their halogenated and oxygen-containing analogs, and N-substitution in the 4-piperidone moiety adds value to the cytotoxicity of the compounds.     

Synthesis of some bisindolyl analogs for in vitro cytotoxic and DNA cleavage studies

One-pot, three components, conventional and microwave-assisted synthesis of bisindolyl analogs is described. Michael addition of preformed 2,5-disubstituted indole-3-carboxaldehydes and 3-methyl-1H-pyrazol-5(4H)-one with 2,5-disubstituted indoles under solvent and catalyst-free conditions afforded the hitherto unreported 2,5-disubstituted bisindolyl analogs bearing a pyrazolone moiety in excellent yields. All the synthesized compounds were characterized using IR, ¹H NMR, mass spectral, and analytical data. The analogs were screened for in vitro cytotoxic and DNA cleavage studies. Among the screened compounds 4c, 4f, and 4h–4j have emerged as most potent cytotoxic and 4c and 4f–4h as active DNA cleavage analogs.     

In-vitro cytotoxicity,antioxidant, bleomycin-dependent DNA damage and immunomodulatory evaluation of 1-(4-acetylphenyl)-3-aryloxypyrrolidine-2, 5-dione based derivatives

A one pot, economical, and efficient synthesis of 1-(4-acetylphenyl)-3-aryloxypyrrolidine-2,5-diones-based derivatives 5a-l have been accomplished in single steps and in satisfactory yields from 1-(4-acetylphenyl)-pyrrole-2,5-diones 3 and phenols 4a–l. All the compounds were characterized by physical, spectroscopic, and elemental analysis. The selection of the bioassays was based on proving the drug receptor binding concept. Compounds 5g, 5k, 5h, 5i, 5a, and 5f showed the highest inhibitory antioxidant activity using ABTS methods. Compounds 5k, 5g, 5c, 5h, 5b, 5d, 5f, and 5j manifested the best protective effect against DNA damage induced by bleomycin. Moreover, an in-vitro cytotoxic activity evaluation of all synthesized compounds was against four cancer cell lines using 5-Fluorouracil as a standard anticancer drug.     

Design and synthesis of niflumic acid-based N-acylhydrazone derivatives as novel anti-inflammatory and analgesic agents

A new series of niflumic acid-based N-acylhydrazone derivatives 5a–p were synthesized and evaluated for their anti-inflammatory and analgesic activities. Most of the compounds have shown anti-inflammatory activity with a moderate-to-excellent activity range (20–80 % reduction in inflammation). Among them, 3-chlorophenyl 5d and 3-pyridyl derivatives 5o exhibited the most potent anti-inflammatory activity relative to niflumic acid as the reference drug (77, 76, and 70 % reduction in inflammation at 1-h postdrug administration, respectively). Also, molecular simplification of niflumic acid through replacing the N-aryl group with N-methyl group produced compounds 6a–f with anti-inflammatory activity in a quite similar manner to those of their parent derivatives. In this subgroup, 4-pyridyl derivative 6f showed the most potent anti-inflammatory activity relative to niflumic acid (80 % reduction in inflammation at 1-h postdrug administration). The compounds with highest anti-inflammatory activity were subjected to analgesic assays and showed moderate-to-excellent analgesic activities. The compound 5j, 4-methoxy derivative, exhibited the highest analgesic activity relative to niflumic acid (97 and 68 % activity, respectively).     

Synthesis of some novel C-5 and N-3 substituted 2-(2-hydroxyphenylimino)thiazolidin-4-one derivatives with broad-spectrum antimicrobial activity

In the present article, compounds 5-((substituted-2-chloroquinolin-3-yl)methylene)-2-(2-hydroxyphenylimino)thiazolidin-4-ones (3a–k), 1-(2-(2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (6) and 1-(2-(5-((substituted-2-chloroquinolin-3-yl)methylene)-2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-triones (8a–k) have been synthesized by substituting C-5 and N-3 position of parent compound 2-(2-hydroxyphenylimino)thiazolidin-4-one (1). Structures of the newly synthesized compounds were assigned on the basis of elemental analyses, IR, ¹H NMR, ¹³C NMR, and mass spectra. In vitro antimicrobial activity of target compounds (3a–k, 6 and 8a–k) was investigated against two Gram-positive, two Gram-negative bacteria and three fungal strains. Among the tested compounds (3e), (3f), and (3h) showed very good antifungal activity, while compound (6) showed very good antibacterial activity. Compounds (8e), (8f), and (8h) showed excellent antifungal and antibacterial activities.     

Schiff’s base derivatives bearing 2-thiophenoxyquinoline nucleus as new antibacterial agents

A series of new Schiff’s base derivatives 4a–x bearing 2-thiophenoxyquinoline nucleus have been designed and synthesized by reaction of 2-thiophenoxyquinoline-3-carbaldehydes 2a–d with various benzohydrazides 3a–f in the presence of Ni(NO₃)₂·6H₂O as a catalyst. In vitro antibacterial screening was carried out against two Gram-positive bacteria (Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538) and two Gram-negative bacteria (Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 13525). Of the compounds studied, compound 4e showed chief activity (MIC = 3.13 μg/mL) against S. aureus, and compounds 4p, 4k, and 4w were found to possess effective antibacterial activity against employed strains compared with standards used. The structures of Schiff’s base derivatives were established by using various spectroscopic methods. A crystal structure of compound 4k has been determined by X-ray diffraction analysis.     

Synthesis, DNA affinity, and antimicrobial activity of 4-substituted phenyl-2,2′-bichalcophenes and aza-analogues

A series of bichalcophene monoamidines 4a–f were synthesized from the corresponding mononitriles 3a–f via a direct reaction with LiN(TMS)₂ followed by deprotection with ethanolic HCl (gas). Bichalcophene mononitriles 3a–f were synthesized via palladium-catalyzed coupling reactions. Thus, a Stille coupling reaction was performed to prepare 6-[5-(thiophen-2-yl)furan-2-yl]nicotinonitrile (3e), when 6-(5-bromofuran-2-yl)nicotinonitrile was allowed to react with 2-n-tributyltin thiophene. The tested bichalcophenes showed a wide range of DNA and protein degradation effect as judged from agarose gel and SDS-PAGE, respectively. Bichalcophenes 3a–f and 4a–f have broad-spectrum antibacterial efficacy being highly active against both Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, and Escherichia coli) bacterial strains. The antifungal activity of these bichalcophene series against Saccharomyces cerevisiae was demonstrated. The MIC of bichalcophenes 3a–f and 4a–f against various microorganisms was also determined. The tested bichalcophenes mimic SOD like activity and inhibited the superoxide radical generation.     

Antimicrobial and antiquorum-sensing studies. Part 2: synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of fused [1,3,4]thiadiazole and [1,3]benzothiazole derivatives

New series of [1,3,4]thiadiazolo[3,2-a]pyrimidines, [1,3,4]thiadiazolo[2,3-b]quinazolines, and pyrimido[2,1-b][1,3]benzothiazoles have been synthesized and characterized by analytical and spectrometrical methods (IR, MS, ¹H, and ¹³C NMR). Sixteen of the synthesized compounds; namely, 3a, b, 5a–f, 8a, b, 10, 11a–c, and 13a, b were screened for antibacterial activity against Escherichia coli, Staphylococcus aureus, and Bacillus cereus. They were found to be either moderately active, slightly active or inactive against the selected microorganisms. The antifungal activity of these compounds were also tested against Candida albicans, Aspergillus fumigatus 293, and Aspergillus flavus 3375. Compound 11a showed potent antifungal activity against the three selected fungi; the rest of the tested compounds displayed either weaker activity or were completely inactive. The same compounds were examined for antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, where compounds 3a, 10, 11a, and 13a, b exhibited promising activity. The in vitro cytotoxic activity of these compounds was also studied by brine shrimp lethality bioassay, and results indicated that compounds 3a, 11a, and 13a have the highest cytotoxic activity.     

Design, synthesis, and biological evaluation of new 4-thiazolidinone derivatives substituted with benzimidazole ring as potential chemotherapeutic agents

In search of novel antiviral and anticancer agents with promising pharmacotoxicological profile, a study was initiated to synthesize new 2-thioxo-4-thiazolidinones as well as 2-phenylimino-4-thiazolidinones substituted with benzimidazole ring system. The compounds were screened primarily for their antiviral as well as anticancer activities. The synthesis of some novel 5-substituted thiazolidinones was also described. None of the tested compounds showed inhibitory activity against Hepatitis C virus replication. Two 2-phenylimino-4-thiazolidinone derivatives (9a and 10) exhibited significant antiproliferative activity against human colon carcinoma cell line HCT 116 and human hepatocellular carcinoma HEPG2 cell line, respectively. Results also indicated that six thiazolidinone derivatives (5a, 5d, 5e, 5f, 5h, and 9d) showed moderate antiproliferative activity against human breast adenocarcinoma cell line MCF7 in comparison to the standard drug Doxorubicin. Moreover, a docked pose of the most potent three cytotoxic compounds 5a, 5h, and 9d against MCF7 was obtained bound to Human N-acetyl transferase1 NAT1 binding pocket by molecular operating environment module.     

Synthesis,antimicrobial, and cytotoxic activities of novel benzimidazole derivatives bearing cyanopyridine and 4-thiazolidinone motifs

A series of 6-(1H-benzo[d]imidazol-2-yl)-2-(2-(3-nitrophenyl)-4-oxothiazolidin-yl)-4-(aryl)nicotinonitriles 5a–l were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, and mass spectrometry techniques. These novel compounds 5a–l were screened for their in vitro antimicrobial activity against different bacterial and fungal strains and in vitro cytotoxicity study (HeLa cell line) using MTT colorimetric assay. The results demonstrated that compounds 5c, 5e, and 5i–k exhibited excellent antibacterial activity, while compounds 5d, 5i, and 5k were found to be the most potent antifungal agents. From the standpoint of SAR studies, it was observed that the presence of electron donating groups remarkably enhanced the antimicrobial activity of newly synthesized compounds. Further, the results of preliminary MTT cytotoxicity studies on HeLa cells suggested that potent antimicrobial activity of 5c–e and 5i–k was accompanied by low cytotoxicity.     

Synthesis and biologic activities of some novel heterocyclic chalcone derivatives

We synthesized 36 chalcone-like (E)-3-(substitutedphenyl)-1-hetrylprop-2-en-1-ones by condensing 2-acetylfuran/2-acetylpyrrole with substituted benzaldehydes under basic conditions. Of the 36 molecules synthesized, 10 are new to the literature. Bio-evaluation studies of these molecules revealed that compounds 5, 9, 15, 25, and 29 were potent NorA efflux pump inhibitors against Staphylococcus aureus by reducing MIC of ciprofloxacin fourfold, while compounds 11, 21, 25, and 26 showed promising anticancer activity in all four tested cancer cell lines (HL-60, MOLT-4, PC-3, and HeLa). Compound 25 emerged as a very good potentiator of ciprofloxacin against multidrug resistant S. aureus and also showed promising anticancer activity. The present communication describes syntheses, bio-evaluation, and structure-related activity of the (E)-3-(substitutedphenyl)-1-hetrylprop-2-en-1-ones.     

Synthesis of B-ring substituted flavones and evaluation of their antitumor and antioxidant activities

A series of flavones, substituted at the ring B, were synthesized using either Claisen–Schimdt Condensation or Baker–Venkataraman rearrangement. The synthesized compounds were tested for in vitro cytotoxic activity by sulforhodamine B assay against three cell lines of different origin, viz. HepG2, MCF-7, and MOLT-4. The compounds were also tested for a possible antioxidant activity by determination of inhibition of lipid peroxidation. Quercetin was taken as a standard for antioxidant activity. Compound 1c showed the highest cytotoxic activity against MCF-7 (GI50 < 0.1 μM) and MOLT-4 (GI50 < 0.1 μM) cell lines and was comparable to adriamycin, the standard used. Compounds 1b, 1g, and 1h also showed promising activity against MCF-7 and MOLT-4 cell lines. In the absence of a hydroxyl group, one or more methoxy groups present on the B-ring (compounds 1c–1e) were major determinants of inhibition of lipid peroxidation.     

Anti-mycobacterial, cytotoxic activities of Knoevenagel and (E)-α,β-unsaturated esters and ketones from 2-chloronicotinaldehydes

Series of 2-chloronicotinaldehyde Knoevenagel derivatives 3a–r; (E)-α,β-unsaturated esters and ketones 5a–k were prepared and evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H₃₇Rv (Mtb). Compounds 3e, 5b, 5d, 5e, 5g and 5i–k were shown potent to significant activity. Compound 5j is the most potent Mtb inhibitor (MIC: 4.89 μM) when compared to standard drugs Ethambutol (MIC: 7.63 μM) and Ciprofloxacin (MIC: 9.44 μM). Eight compounds displayed potent/significant activity against M. tuberculosis were chosen for the cytotoxicity against three cell lines (Raw 264.7, MCF7, and HeLa). Compound 5j displayed low toxicity with high selective index (15–30) and is an interesting new compound may serve for the development of therapeutics targeted against anti-mycobacterial compounds. This is the first report assigning in vitro anti-mycobacterial inhibitory activity and structure–activity relationship for this class of substituted 2-chloronicotinaldehyde derivatives and presents new family of compounds.     

Synthesis of new olefin chalcone derivatives as antitumor, antioxidant and antimicrobial agents

Chalcone is a unique template that is associated with several biological activities. Claisen–Schmidt condensation of olefin aldehyde 3 and various mono, disubstituted and heterocyclic acetophenones afforded novel olefin chalcones. Synthesized compounds were subjected for ADME prediction by computational method which revealed that these molecules can be considered as a potential drug. Out of the 21 compounds screened, compounds 5u, 5g, 5c and 5e have shown significant cytotoxicity against Hep 3BPN 7, compounds 5j, 5i, 5n and 5o showed good cytotoxicity against HL 60 P 58. Compounds 5f, 5c, 5e and 5b showed potent cytotoxicity against Hela B 75. Antioxidant activity was assessed using three methods, namely, 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl radical scavenging and ferric reducing antioxidant power (FRAP). The result shows that all these compounds possess significant antioxidant activity. Compounds 5k, 5s, 5a and 5c showed promising antibacterial activity. Compounds 5k, 5u and 5f could be considered as chemopreventive agents.     

Synthesis and biological evaluation of some N 4-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones

A series of N ⁴-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones 3a–3l was synthesized and evaluated for selected biological activities. The brine shrimp lethality bioassay was carried out to study their in vitro cytotoxicity potential and besides, their antifungal, phytotoxic and urease inhibitory effects were also investigated. Seven compounds i.e. 3a, 3d, 3f, 3g, 3h, 3j and 3k proved to be active in the brine shrimp assay, displaying promising cytotoxicity (LD₅₀ = 6.89 × 10^?5–2.79 × 10^?4 M). Amongst these, 3a and 3h were found to be the most active ones (LD₅₀ = 6.89 × 10^?5 and 9.79 × 10^?5 M, respectively). Compounds 3i, 3j and 3 k displayed moderate (40 %) antifungal activity against one or two fungal strains i.e. A. flavus and/or M. canis. In phytotoxicity assay, all the synthesized compounds, including the reference point 2m showed weak-to-moderate (15–70 %) activity at the highest tested concentration (500 μg/mL). In urease inhibition assay, compounds 3f, 3g and 3j proved to be the most potent inhibitors, demonstrating relatively a higher degree of enzymatic inhibition with IC₅₀ values ranging from 37.7 to 47.3 μM.