Synthesis,Characterization and In Vitro Evaluation of Novel 5-Ene-thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones as Possible Anticancer Agents

The present paper is devoted to the search for drug-like molecules with anticancer properties using the thiazolo[3,2-b][1,2,4]triazole-6-one scaffold. A series of 24 novel thiazolo-[3,2-b][1,2,4]triazole-6-ones with 5-aryl(heteryl)idene- and 5-aminomethylidene-moieties has been synthesized employing three-component and three-stage synthetic protocols. A mixture of Z/E-isomers was obtained in solution for the synthesized 5-aminomethylidene-thiazolo[3,2-b]-[1,2,4]triazole-6-ones. The compounds have been studied for their antitumor activity in the NCI 60 lines screen. Some compounds present excellent anticancer properties at 10 μM. Derivatives 2h and 2i were the most active against cancer cell lines without causing toxicity to normal somatic (HEK293) cells. A preliminary SAR study had been performed for the synthesized compounds.     

Synthesis and anticancer evaluation of some new pyrazolo[3,4-d][1,2,3]triazin-4-ones,pyrazolo[1,5-a]pyrimidines,and imidazo[1,2-b]pyrazoles clubbed with carbazole

Carbazole represents as a promising template for cancer treatment as it exists in the skeleton of numerous man-made and natural anticancer agents. In this regard, new sets of novel functionalized pyrazolo[3,4-d][1,2,3]triazin-4-ones 6a-e and 10a-e , pyrazolo[1,5-a]pyrimidines 16a,b and imidazo[1,2-b]pyrazoles 20a,b and 23a-c having carbazole moiety were efficiently synthesized, characterized, and mechanistically discussed. They were also evaluated against three human cancer cell lines (HCT-116, HepG-2, and MCF-7) and one standard human cell line (REP1) for their in vitro anticancer activity. The results declared that seven compounds 10d , 10e , 12b , 12d , 12e , 16a , and 23a had potent anticancer activity, having IC₅₀ values in the range 2.97 to 10.31 μM. The most effective compounds 10d and 10e inhibited the growth of all screened cancer cell lines and did not reveal human toxicity.     

Synthesis and Anticancer Activity Evaluation of 5-[2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-thiazolidinones

A series of novel 5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-thiazolidinones (Ciminalum–thiazolidinone hybrid molecules) have been synthesized. Anticancer activity screening toward the NCI60 cell lines panel, gastric cancer (AGS), human colon cancer (DLD-1), and breast cancer (MCF-7 and MDA-MB-231) cell lines allowed the identification of 3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid (2h) with the highest level of antimitotic activity with mean GI₅₀/TGI values of 1.57/13.3 μM and a certain sensitivity profile against leukemia (MOLT-4, SR), colon cancer (SW-620), CNS cancer (SF-539), melanoma (SK-MEL-5), gastric cancer (AGS), human colon cancer (DLD-1), and breast cancers (MCF-7 and MDA-MB-231) cell lines. The hit compounds 2f, 2i, 2j, and 2h have been found to have low toxicity toward normal human blood lymphocytes and a fairly wide therapeutic range. The significant role of the 2-chloro-3-(4-nitrophenyl)prop-2-enylidene (Ciminalum) substituent in the 5 position and the substituent’s nature in the position 3 of core heterocycle in the anticancer cytotoxicity levels of 4-thiazolidinone derivatives have been established     

Synthesis and antitumor activities of a new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives

A new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives have been designed and synthesized.The antitumor activities of the target compounds have been evaluated in vitro against two human cancer cell lines including A549 (human alveolar adenocarcinoma cell) and H460 (human lung cancer) by MTT assay.Most of the target compounds exhibited significant antitumor activities against A549 and H460 cancer cell lines.The most potent compound 4-(benzo[d][1,3]dioxol5-yl)-8,9-difluoro-2-(4-methylpiperazin-1-yl)-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH05) (IC50=0.44 M,3.07 M) was 2.0 and 8.4 times more active than gefitinib (IC50=0.89 M,16.81 M) against A549 and H460 cell lines,respectively.     

Synthesis and Anticancer Evaluation of Some Novel Thiophene,Thieno[3,2‐d]pyrimidine,Thieno[3,2‐b]pyridine,and Thieno[3,2‐e][1,4]oxazepine Derivatives Containing Benzothiazole Moiety

In an attempt to establish novel candidate with promising anticancer activity, two derivatives of (benzo[d]thiazol‐2‐yl)thiophene backbone 1 and 14 were synthesized, and they further reacted with various chemical reagents to afford the corresponding substituted thiophene derivatives 6 , 8 , 10 , 15 , 17 , and 20 , thieno[3,2‐d]pyrimidine derivatives 2 – 5 , 7 , 9 , 16 , 21 , 23 , and 24 , thieno[3,2‐b]pyridine derivatives 11 – 13 , and thieno[3,2‐e][1,4]oxazepine derivative 18 . Structures of prepared compounds were affirmed via spectral and elemental data. Among the obtained compounds, seven derivatives 2 , 3 , 4 , 5 , 11 , 12 , and 13 were chosen by National Cancer Institute, USA. Such compounds were screened for their antitumor activity versus 60 cancer cell lines in one‐dose (10 μmol) screening assay. The outcomes showed that all selected compounds exhibited moderate to high anticancer activity towards many cancer cell lines among which compounds 5 and 11 exerted potent antitumor activity against numerous malignant growth cell lines particularly Ovarian Cancer IGROV1.     

Design, synthesis and antiproliferative activities of novel 5H-pyridazino[4,5-b]indoles

A novel series of 5H-pyridazino[4,5-b]indoles were designed and synthesized in order to find novel potent anticancer compounds.The structures were confirmed by ~1H NMR and MS.Their antiproliferative activities against two cancer cell lines were tested by the MTT method in vitro.Three of compounds (1e,1g,and 1h) exhibited potent antiproliferative activities,especially compound 1h (with IC_(50) values of 5.2μmol/L and 1.9μmol/L against Bel-7402 and HT-1080,respectively).The preliminary structure-activity relationships of 5H-pyridazino[4,5-b]indole derivatives were discussed.     

新型[1,2,4]三唑[4,3-b]均四嗪类化合物的合成及其抗癌活性

以6-(3,5-二甲基吡唑-1-基)-3-肼基均四嗪和芳醛为原料,经Schiff碱缩合和环合反应合成了6个新型的6-芳基-3-(3,5-二甲基吡唑-1-基)[1,2,4]三唑[4,3-b]均四嗪类化合物(4a～4f),其结构经1HNMR,MS,IR和元素分析表征。以顺铂为对照,采用MTT法测试了体外4a～4f对人白血病细胞株,人肺癌,人乳腺癌和人子宫颈癌细胞株的抗癌活性。结果表明,4a～4f对四种癌细胞均具有较强的抑制活性。     

Synthesis and Antimicrobial,Anticancer and Anti-Oxidant Activities of Novel 2,3-Dihydropyrido[2,3-d]pyrimidine-4-one and Pyrrolo[2,1-b][1,3]benzothiazole Derivatives via Microwave-Assisted Synthesis

In our attempt towards the synthesis and development of effective antimicrobial, anticancer and antioxidant agents, a novel series of 2,3-dihydropyrido[2,3-d]pyrimidin-4-one 7a–e and pyrrolo[2,1-b][1,3]benzothiazoles 9a–e were synthesized. The synthesis of 2-(1,3-benzo thiazol-2-yl)-3-(aryl)prop-2-enenitrile (5a–e) as the key intermediate was accomplished by a microwave efficient method. Via a new variety oriented synthetic microwave pathway, these highly functionalized building blocks allowed access to numerous fused heteroaromatic such as 7-amino-6-(1,3-benzo thiazol-2-yl)-5-(aryl)-2-thioxo-2,3dihydropyrido [2,3-d]pyrimidin-4(1H)-one 7a–e and 1-amino-2-(aryl)pyrrolo[2,1-b][1,3]benzothiazole-3-carbonitrile derivatives 9a–e in order to study their antimicrobial and anticancer activity. The present investigation offers effective and rapid new procedures for the synthesis of the newly polycondensed heterocyclic ring systems. All the newly synthesized compounds were evaluated for antimicrobial, anticancer and antioxidant activity. Compounds 7a,d, and 9a,d showed higher antimicrobial activity than cefotaxime and fluconazole while the remaining compounds exhibited good to moderate activity against bacteria and fungi. An anticancer evaluation of the newly synthesized compounds against the three tumor cell lines (lung cell NCI-H460, liver cancer HepG2 and colon cancer HCT-116) exhibited that compounds 7a, d, and 9a,d have higher cytotoxicity against the three human cell lines compared to doxorubicin as a reference drug. These compounds also exhibited higher antioxidant activity and a great ability to protect DNA from damage induced by bleomycin.     

Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide derivatives were prepared as potential antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was investigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDA-MB-468) cells. Structure–activity relationship studies revealed that xanthone benzenesulfonamide hybrid compounds can be used for the development of new lead anticancer agents.     

One-pot synthesis and biological evaluation of novel 4-[3-fluoro-4-(morpholin-4-yl)]phenyl-1H-1,2,3-triazole derivatives as potent antibacterial and anticancer agents

In search of better antibacterial and anticancer agents, a series of novel 4-[3-fluoro-4-(morpholin-4-yl)]phenyl-1H-1,2,3-triazole derivatives were synthesized ( 6a - l and 8a - j ) by using 3-fluoro-4-morpholinoaniline, alkyne, and triflyl azide via an in situ generated 4-(4-azido-2-fluorophenyl)morpholine and evaluated for their antibacterial and anticancer activity in vitro. Antibacterial activity against three G+ bacterial strains and anticancer activity against breast cancer cell line (MCF-7) and cervical carcinoma cell line (HeLa) was evaluated. Among all the tested compounds, 6h , 6i , and 8b exhibited potent antibacterial activity against tested gram-positive bacterial strains. The anticancer activity screening results of 8f , 8h , and 8i exhibited potent cytotoxic activity against two cancer cell lines with IC₅₀ values nearer to the standard drug, doxorubicin. The remaining compounds have shown good to moderate activity against the tested cell lines. On the basis of the results obtained, a structure-activity relationship (SAR) is discussed.     

Syntheses and antibacterial studies of some 2-[5-(Aryl)-[1,3,4]oxadiazole-2-ylsulfanyl] alkanoic Acids

Some new 2-[5-(aryl)-[1,3,4]oxadiazole-2-ylsulfanyl]alkanoic acids were synthesized and studied for their antibacterial activity. These compounds were prepared from aromatic carboxylic acid hydrazides. Aromatic carboxylic acid hydrazides 1 on refluxing with carbon disulfide and methanolic potassium hydroxide and then on subsequent acidification with hydrochloric acid furnish 5-aryl-1,3,4-oxadiazole-2-thiones 2. 2-Chloro alkanoic acids react with 2 in alkaline media and on acidification yield the title compounds 3. These compounds were characterised by CHN analyses, IR, mass and ¹H NMR spectral data. All the compounds were evaluated for their in vitro antibacterial activity against two Gram negative strains (Escherichia coli and Pseudomonas aeruginosa) and two Gram positive strains (Bacillus subtilis and Staphylococcus aureus) and their minimum inhibitory concentration (MIC) were determined.     

Synthesis and antibacterial activity of novel [1,2,4]triazolo [3,4-h][1,8]naphthyridine-7-carboxylic acid derivatives

Novel tricyclic fluoroquinolones,[1,2,4]triazolo[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives 4a-4h bearing carrying a functional Mannich-base moiety at the C-8 position,were synthesized and evaluated for their antimicrobial activity.The results showed that some compounds with a piperazine side chain exhibited comparable or better antibacterial activity than comparator cirprofloxacin.Furthermore,the targeted compounds also displayed a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria.In particular,compound 4h showed an MIC of 0.25 μg/mL in antibacterial assay against multiple drug-resistant Escherichia coli,which represents an about 30-fold increase of potency compared to ciprofloxacin.Thus,their excellent antibacterial activity against resistant strains suggests that triazole-fused fluoroquinolones warrant further optimization as novel anti-infective chemotherapies.     

Synthesis of novel isoxazole functionalized pyrazolo[3,4-b]pyridine derivatives; their anticancer activity

A series of novel isoxazole functionalized pyrazolo[3,4-b]pyridine derivatives 5a-n were prepared, respectively, initiated from 6-thiophenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 3 through selective N-propargylation, and these N-propargylated compounds 4 were cyclized with aryloximes by using of sodium hypochlorite, and obtained the title products 5a-n . All the final products 5a-n were submitted for anticancer activity against four cancer cell lines such as “HeLa—cervical cancer (CCL-2); COLO 205—colon cancer (CCL-222); HepG2—liver cancer (HB-8065); MCF7—breast cancer (HTB-22)”; Compounds 5c , 5d , and 5h are found to have more prominent anticancer activity at micro molar concentration.     

Synthesis and Biological Evaluation of Novel 5,7-Diphenylimidazo[1,2-a]pyridine Derivatives

A series of novel 5,7-diphenylimidazo[1,2-a]pyridine derivatives was designed and synthesized. The in vitro cytotoxic activities of all the target compounds against human colorectal cancer（HT-29）, human lung can- cer（H460）, human gastric cancer（MKN45） and human breast cancer（MDA-MB-231） cell lines were evaluated. The pharmacological results indicated that most of the target compounds showed moderate to excellent activities against the tested cell lines. The most promising compound 4h（0.20, 0.006, 0.08, 0.021 μmol/L） was 2.6, 5.1, 3.6 and 21.9 times more active than EPC2407（0.52, 0.031, 0.29, 0.46 μmol/L） against HT-29, H460, MKN45 and MDA-MB-231 cell lines, respectively.     

Synthesis of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one

Derivatives of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one were prepared in four steps starting from substituted benzonitriles bearing a functionalized amino group in the adjacent position. The unsubstituted- and the dimethoxy-pyrrolizinoindolones 5a and 5b exhibited modest activity against the HL-60(TB) human leukemia cell line, whereas the N-methylated dimethoxy-pyrrolizinoindolone 6b showed to be selective against MOLT-4 leukemia, A549/ATCC, HOP-92, and NCI-H460 non-small cell lung cancer, and CAKI-1 renal cancer cell lines.     

CuSO4/sodium ascorbate catalysed synthesis of benzosuberone and 1,2,3-triazole conjugates: Design,synthesis and in vitro anti-proliferative activity

A novel series of conjugates of benzosuberone and 1,2,3-triazole i.e. 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl-9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylic acids (8a-j) were synthesized in good to excellent yields catalysed by CuSO₄ under milder reaction conditions and evaluated for their anti-proliferative activity. The structural elucidation of the prepared compounds was carried out using IR, ¹H NMR, ¹³C NMR and Mass spectral analysis. The newly synthesized derivatives (8a-j) were evaluated for their anti-proliferative activity against four human cell lines and the novel derivatives showed moderate to excellent activity. The obtained results suggest that these compounds can be considered as new hits for anti-proliferative drug development programme and further SAR studies can help obtain better anticancer agents.     

Synthesis and biological activity of fluorinated 7-aryl-2-pyridyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amines

In our lead finding program, 12 new fluorinated 7-aryl-2-pyridyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amines were prepared via a practical three-step procedure starting from (iso)nicotinic hydrazides. The fluorine substituted aryl fragment was introduced in the last step through cyclocondensation of N-(3-pyridyl-1,2,4-triazol-5-yl)guanidines and fluoro/trifluoromethyl substituted benzaldehydes. The structures of the compounds were confirmed by ¹H and ¹³C NMR spectral data. The tautomeric preferences for the compounds were established using 2D NOESY experiments. The antiproliferative activity of the synthesized 1,2,4-triazolo[1,5-a][1,3,5]triazines was evaluated against breast, colon and lung cancer cell lines. The highest antiproliferative activity in the series was found for 2-(pyridine-3-yl)-7-(4-trifluoromethylphenyl)-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amine. The lack of inhibitory activity against bovine dihydrofolate reductase (DHFR) indicated that the antiproliferative activity was realized via other mechanisms.     

Synthesis and Bioactivity Evaluation of New 6-Aryl-5-cyano Thiouracils as Potential Antimicrobial and Anticancer Agents

Several novel 6-aryl-5-cyano thiouracil derivatives were synthesized and explored for their activities as antibacterial, antifungal and anticancer agents. The antimicrobial evaluation revealed that compounds 7b and 7c possessed superior antibacterial activity against the Gram positive bacteria S. aureus and B. subtilis compared to the reference drug amoxicillin. Moreover, compound 4i was found to be a broad spectrum antimicrobial agent and it also exhibited the highest antifungal activity against C. albicans, even higher than the reference drug amphotericin B (MIC = 2.34, 3.00 μg/mL respectively). Selected compounds were tested for in vitro cytotoxicity at a single 10^-5 M concentration in accordance to the NCI (USA) protocol. The preliminary screening results showed that most of the compounds had limited cytotoxic activity against renal cancer UO-31 and/or A498 cell lines. Nevertheless, compounds 6d and 6i displayed potent growth inhibitory effect toward non-small cell lung cancer HOP-92 and leukemia MOLT-4 cell lines, respectively.     

Synthesis,Antibacterial and Antifungal Activity of New 3-Aryl-5H-pyrrolo[1,2-a]imidazole and 5H-Imidazo[1,2-a]azepine Quaternary Salts

A series of novel 3-aryl-5H-pyrrolo[1,2-a]imidazole and 5H-imidazo[1,2-a]azepine quaternary salts were synthesized in 58–85% yields via the reaction of 3-aryl-6, 7-dihydro-5H-pyrrolo[1,2-a]imidazoles or 3-aryl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepines and various alkylating reagents. All compounds were characterized by ¹H NMR, ¹³C NMR, and LC-MS. The conducted screening studies of the in vitro antimicrobial activity of the new quaternary salts derivatives established that 15 of the 18 newly synthesized compounds show antibacterial and antifungal activity. Synthesized 3-(3,4-dichlorohenyl)-1-[(4-phenoxyphenylcarbamoyl)-methyl]-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-1-ium chloride 6c possessed a broad activity spectrum towards Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Cryptococcus neoformans, with a high hemolytic activity against human red blood cells and cytotoxicity against HEK-293. However, compound 6c is characterized by a low in vivo toxicity in mice (LD₅₀ > 2000 mg/kg).     

Synthesis and Anticancer Evaluation of Some Novel 5‐Amino[1,2,4]Triazole Derivatives

Novel [1,2,4]triazole derivatives were synthesized via various synthetic pathways. Among which were different substituted [1,2,4]triazole analogues that were synthesized, in addition to various fused [1,2,4]triazolo[1,5‐a]pyrimidine derivatives, [1,2,4]triazolo[1,5‐a][1,3,5]triazines, and [1,2,4]triazolo[5,1‐c][1,2,4]triazines. Besides, benzo[h][1,2,4]triazolo[5,1‐b]quinazolines, [1,2,4]triazolo‐[5,1‐b]quinazoline, [1,2,4]triazolo[1,5‐a]quinazoline and [1,2,4]triazolo[5,1‐d][1,2,3,5]tetrazine derivatives were also synthesized. The newly synthesized compounds were evaluated for their in vitro anticancer activity against liver cancer HepG2 and breast cancer MCF7 cell lines compared with the reference drug doxorubicin. Compounds 4 , 7 , 15 , 17 , 28 , 34 , and 47 were found to exert promising anticancer activity against HepG2 cell line showing IC₅₀ values ranging from 17.69 to 25.4 μM/L, while compounds 7 , 14a , 17 , 28 , and 34 showed significant activity against MCF7 cell line with IC₅₀ values ranging from 17.69 to 27.09 μM/L.