Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via one-pot multi-component reaction as potent cytotoxic agents against cancer cell lines

In this study, twenty-five (25) substituted aryl thiazoles (SAT) 1–25 were synthesized, and their in vitro cytotoxicity was evaluated against four cancer cell lines, MCF-7 (ER^+ve breast), MDA-MB-231 (ER^−ve breast), HCT116 (colorectal) and HeLa (cervical). The activity was compared with the standard anticancer drug doxorubicin (IC₅₀ = 1.56 ± 0.05 μM). Among them, compounds 1, 4–8, and 19 were found to be toxic to all four cancer cell lines (IC₅₀ values 5.37 ± 0.56–46.72 ± 1.80 μM). Compound 20 was selectively active against MCF7 breast cancer cells with IC₅₀ of 40.21 ± 4.15 μM, whereas compound 19 was active against MCF7 and HeLa cells with IC₅₀ of 46.72 ± 1.8, and 19.86 ± 0.11 μM, respectively. These results suggest that substituted aryl thiazoles 1 and 4 deserve to be further investigated in vivo as anticancer leads.     

Synthesis and cytotoxic evaluation of a series of genistein derivatives

Thirty genistein (= 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; GEN) derivatives were synthesized from genistein through a facile approach in high yields. Compounds 9, 11, 12, 23-30 were reported for the first time, while 13-22 have already been reported in our recent paper. The cytotoxic activities of these compounds were evaluated against a human nasopharyngeal epidermoid tumor cell line KB. Compounds 7-9, 12, 14, 16-19, 21, 24, 27, 29 showed remarkable antitumor activities in vitro, which was comparable with 5-fluorouracil, an anticancer drug. On the basis of the obtained experimental data, structure-effect relationships were discussed.     

Synthesis and antitumor activity of biotinylated camptothecin derivatives as potent cytotoxic agents

A series of biotinylated camptothecin derivatives were designed and synthesized. The key to the synthesis was achieved by employing an esterification reaction and click chemistry. All of the new derivatives were tested for cytotoxicity against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC₅₀ values ranging from 0.13 to 21.53?μM. Most of the derivatives exhibited potent cytotoxicity, especially compound 17 (IC₅₀?=?0.13–3.31?μM) and compound 18 (IC₅₀?=?0.23–1.48?μM), which exhibited the highest potencies. The structure-activity relationships (SARs) of the biotinylated camptothecin derivatives were discussed for exploring novel anticancer agents.     

Synthesis and cytotoxic evaluation of novel 7-O-modified genistein derivatives

Two series of genistein (=5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) derivatives with heterocycles were prepared, in which genistein and heterocyclic moieties were separated by C(2) and C(3) spacers. Among the 24 compounds we prepared, 22, i.e., 3a-3k and 4a-4k, were reported for the first time, while the preparation of 2a and 2b was reported in our recent paper. The cytotoxic activities of these compounds were evaluated against human chronic myeloid leukemia cells (K562) and a human nasopharyngeal epidermoid tumor cell line (KB). Compounds 4a, 4d, 4e, 4h, and 4i showed remarkable anticancer activities in vitro that are comparable with 5-fluorouracil, an canonical anticancer drug. Structure-effect relationships were also discussed based on the experimental data obtained.     

Design and synthesis of novel spin-labeled camptothecin derivatives as potent cytotoxic agents

In our continuing search for natural product-based spin-labeled antitumor drugs, 20 novel spin-labeled camptothecin derivatives were synthesized via a Cu-catalyzed one pot reaction and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). Eighteen of the target compounds (9a, 9b, 9d–9k, 9m–9t) exhibited significant in vitro antiproliferative activity against these four tested tumor cell lines. Compounds 9e and 9j (IC₅₀ 0.057 and 0.072 μM, respectively) displayed the greatest cytotoxicity against the multidrug-resistant (MDR) KBvin cell line and merit further development into preclinical and clinical drug candidates for treating cancer including MDR phenotype.     

Design,synthesis and biological evaluation of novel semicarbazone-selenochroman-4-ones hybrids as potent antifungal agents

A series of novel 2,3-dihydro-4H-1-benzoselenin-4-one (thio)semicarbazone derivatives were designed and synthesized by using molecular hybridization approach. All the target compounds were characterized by HRMS and NMR and evaluated in vitro antifungal activity against five pathogenic strains. In comparison with precursor selenochroman-4-ones, the hybrid molecules in this study showed significant improvement in antifungal activities. Notably, compound B8 showed significant antifungal activity against other strains excluding Aspergillus fumigatus (0.25 μg/mL on Candida albicans, 2 μg/mL on Cryptococcus neoformans, 8 μg/mL on Candida zeylanoides and 2 μg/mL on fluconazole-sensitive strains of Candida albicans). Moreover, compounds B8, B9 and C2 also displayed most potent activities against four fluconazole-resistance strains. Especially the MIC values of the hybrid molecule B8 against fluconazole-resistant strains were in the range of 0.5–2 μg/mL. Therefore, the molecular hybridization approach in this study provided new ideas for the development of antifungal drug.     

Synthesis and cytotoxic evaluation of a series of resveratrol derivatives

A total of 17 resveratrol (=(E)-5-[2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol) derivatives were synthesized from resveratrol (RES) through a facile approach. Among them, 13 compounds, 2 and 6-17, were reported for the first time, while 1 and 3-5 had already been reported several years ago. The cytotoxic activities of these compounds were evaluated against human nasopharyngeal epidermoid tumor cell line KB, and compounds 1 and 8-11 showed strong anticancer activities in vitro, comparable with that of 5-fluorouracil, an anticancer drug. On the basis of the experimental data obtained, structure-activity relationships are discussed.     

Design and synthesis of aminocoumarin derivatives as DPP-IV inhibitors and anticancer agents

DPP-IV “a moonlighting protein” has immerged as promising pathway to control Type 2 diabetes as well as found to play key role in earlier stages of cancer. Here we have reported design, synthesis and applications of aminocoumarin derivatives as DPP-IV inhibitors. Compounds have been synthesized and studied for their DPP-IV inhibition activity. Three compounds have shown moderate inhibition at 100 µM concentration. All compounds were also screened for their anticancer activity against A549 (Lung cancer cell line), MCF-7 (Breast cancer cell line) using MTT assay. One of the compounds has shown very good anticancer activity with IC₅₀ value 24 ± 0.1 nM against A549 cell line.     

Design and synthesis of novel imidazo[4,5-b]pyridine based compounds as potent anticancer agents with CDK9 inhibitory activity

New imidazo[4,5-b]pyridine derivatives were designed, synthesized and screened for their anticancer activity against breast (MCF-7) and colon (HCT116) cancer cell lines. Nine compounds (I, II, IIIa, IIIb, IV, VI, VIIa, VIII, IX) showed significant activity against MCF-7, while six compounds (I, VIIc, VIIe, VIIf, VIII, IX) elicited a remarkable activity against HCT116. Compounds showing significant anticancer activity revealed remarkable CDK9 inhibitory potential (IC₅₀ = 0.63–1.32 μM) relative to sorafenib (IC₅₀ = 0.76 μM). Moreover, a molecular docking study was performed to illustrate the binding mode of the most active compounds in the active site of CDK9 where it revealed superior binding affinity relative to the natural ligand (T3C).     

Design and synthesis of new 7-(N-substituted-methyl)-camptothecin derivatives as potent cytotoxic agents

A series of novel 7-(N-substituted-methyl)-camptothecin derivatives was designed, synthesized, and evaluated for in vitro cytotoxicity against four human tumor cell lines, A-549, MDA-MB-231, KB, and KBvin. All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, with IC₅₀ values ranging from 0.0023 to 1.11 μM, and were as or more potent than topotecan. Compounds 9d, 9e, and 9r exhibited the highest antiproliferative activity among all prepared derivatives. Furthermore, all of the compounds were more potent than paclitaxel against the multidrug-resistant (MDR) KBvin subline. With a concise efficient synthesis and potent cytotoxic profiles, especially significant activity towards KBvin, compounds 9d, 9e, and 9r merit further development as a new generation of camptothecin-derived anticancer clinical trial candidates.     

Design,synthesis and evaluation of biphenyl imidazole analogues as potent antifungal agents

To further explore the structure activity relationships (SARs) of our previously discovered antifungal lead compound (1), a series of biphenyl imidazole analogues were designed, synthesized and evaluated for their in vitro antifungal activity. Many of the synthesized compounds showed excellent activity against Candida albicans and Candida tropicalis. Among these compounds, 2-F substituted analogue 12m displayed the most remarkable in vitro activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and itraconazole. Notably, the compound 12m exhibited low inhibition profiles for various human cytochrome P450 isoforms and showed low toxicity to mammalian A549 cells and U87 cells. The SARs and binding mode established in this study will be useful for further lead optimization.     

Hybrid pharmacophore design and synthesis of isatin–benzothiazole analogs for their anti-breast cancer activity

A hybrid pharmacophore approach was used to design and synthesize isatin–benzothiazole analogs to examine their anti-breast cancer activity. The cytotoxicity of these compounds were determined using three different human breast tumor cell lines, MDA-MB231, MDA-MB468, MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Although all compounds examined were quite effective on all the cancer cell lines examined, the compounds 4-bromo-1-diethylaminomethyl-1H-indole-2,3-dione (2l) and 4-chloro-1-dimethylaminomethyl-3-(6-methyl-benzothiazol-2-ylimino)-1,3-dihydro-indol-2-one (5e) emerged as the most active compounds of this series. Importantly, the cytotoxic effect of 2l was 10–15-fold higher on cancer than non-cancer cells, suggesting that this compound can be very effective for the control of breast cancer with low side effects. Since 2l showed effective cytotoxicity on MCF7 cells and arrested the cells at G2/M at a similar concentration, these two phenomena may be closely correlated. We conclude that the isatin-linked benzothiazole analog can serve as a prototype molecule for further development of a new class of anti-breast cancer agents.     

Synthesis and biological evaluation of ethacrynic acid derivatives bearing sulfonamides as potent anti-cancer agents

A series of ethacrynic acid (2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid) (EA, Edecrin) containing sulfonamides linked via three types of linkers namely 1,2-ethylenediamine, piperazine and 4-aminopiperidine was synthesized and subsequently evaluated in vitro against HL60 and HCT116 cancer cell lines. All the EA analogs, excluding 6a and 6c, showed anti-proliferative activity with IC_50s in the micromolar range (less than 4 uM). Three derivatives 6b, 7b and 7e were selected for their interesting dual activity on HL60 cell line in order to be further evaluated against a panel of cancer cell lines (HCT116, A549, MCF7, PC3, U87-MG and SKOV3) as well as on MRC5 as a normal cell line. These compounds displayed IC₅₀ values in nanomolar range against A549, MCF7, PC3 and HCT116 cell lines, deducing the discovery that piperazine or 4-aminopiperidine is the linker’s best choice to develop EA analogs with highly potent anti-proliferative activities own up to 24 nM. Besides, in terms of selectivity, those linkers are more suitable offering safety ratios of up to 63.8.     

Identification of novel HDAC inhibitors through cell based screening and their evaluation as potential anticancer agents

A series of benzimidazole based HDAC inhibitors have been rationally designed, synthesized and screened. The SAR of this new chemotype is described. The lead compound, 11e, showed strong activity in several cellular assays and demonstrated in vivo efficacy in mouse xenograft pancreatic cancer models.     

Design,synthesis, and pharmacological evaluation of novel oxadiazole and oxadiazoline analogs as anti-inflammatory agents

Two novel series of oxadiazole and oxadiazoline analogs possessing an indole nucleus were synthesized for their potential anti-inflammatory activity. The structures of the compounds were elucidated by elemental and spectral (IR, ¹H-NMR, ¹³C-NMR, and MS) analysis. Most of the test compounds demonstrated appreciable anti-inflammatory activities. The anti-inflammatory activity of oxadiazoles at doses of 100?mg/kg was shown by their ability to provide 27–66%, 14–32%, and 20-51%. protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. On the other hand, the anti-inflammatory properties of oxadiazolines at doses of 100?mg/kg were reflected by their ability to provide 20-56%, 11–26%, and 25–47% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. The ulcerogenic potential of the compounds was determined. Structure–activity relationships among synthesized compounds were also established.     

Design,synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51

To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC–MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.     

Design,synthesis and evaluation of carbazole derivatives as potential antimicrobial agents

Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5–2 µg/ml). Furthermore, compounds 8b, 8d, 8f, 8k, 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure–activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.     

Design,synthesis and biological evaluation of 4-benzoyl-1-dichlorobenzoylthiosemicarbazides as potent Gram-positive antibacterial agents

Twelve 4-benzoyl-1-dichlorobenzoylthiosemicarbazides have been tested as potential antibacterials. All the compounds had MICs between 0.49 and 15.63?µg/ml toward Micrococcus luteus, Bacillus cereus, Bacillus subtilis and Staphylococcus epidermidis indicating, in most cases, equipotent or even more effective action than cefuroxime. In order to clarify if the observed antibacterial effects are universal, further research were undertaken to test inhibitory potency of two most potent compounds 3 and 11 on clinical isolates of Staphylococcus aureus. Compound 11 inhibited the growth of methicillin-sensitive S. aureus (MSSA) at MICs of 1.95–7.81?µg/ml, methicillin-resistant S. aureus (MRSA) at MICs of 0.49–1.95?µg/ml and MDR–MRSA at MIC of 0.98 and 3.90?µg/ml, respectively. Finally, inhibitory efficacy of 3 and 11 on planktonic cells and biofilms formation in clinical isolates of S. aureus and Haemophilus parainfluenzae was tested. The majority of cells in biofilm populations of MSSA and MRSA were eradicated at low level of 3, with MBICs in the range of 7.82–15.63?µg/ml.     

Synthesis,biological evaluation and virtual screening of some acridone derivatives as potential anticancer agents

Eleven novel acridone derivatives were synthesized and evaluated for their anticancer activity against 60 human cancer cell lines. Five compounds 8b, 8d, 8g, 8h, and 8k displayed very good in vitro antiproliferative activities well over 95% of the panels. The most active compound is 8k (5, 7-dibromo-3-phenyl-3,4-dihydroacridin-1 (2H)-one). In addition, 8k was the most sensitive agent in all 9 panels starting with prostate (0.075 µm), leukemia (0.116 µm), non-small cell lung cancer (0.164 µm), colon cancer (0.193 µm), CNS cancer (0.264 µm), melanoma (0.317 µm), renal cancer (0.403 µm), ovarian cancer (0.410 µm), and breast cancer (0.608 µm). Virtual screening studies also revealed that nine of the eleven compounds formed good binding interaction with the active site ATPase domain of human topoisomerase IIα (PDB: 1zxm). All nine derivatives exhibited binding affinities that ranged in values from −8.5 to −7.9 kcal/mol, indicating that they could be catalytic inhibitors of the nuclear enzyme, topoisomerase.     

Synthesis and evaluation of naphthyl bearing 1,2,3-triazole analogs as antiplasmodial agents,cytotoxicity and docking studies

Novel series of naphthyl bearing 1,2,3-triazoles (4a–t) were synthesized and evaluated for their in vitro antiplasmodial activity against pyrimethamine (Pyr)-sensitive and resistant strains of Plasmodium falciparum. The synthesized compounds were assessed for their cytotoxicity employing human embryonic kidney cell line (HEK-293), and none of them was found to be toxic. Among them 4j, 4k, 4l, 4m, 4n, 4t exhibited significant antiplasmodial activity in both strains, of which compounds 4m, 4n and 4t (～3.0-fold) displayed superior activity to Pyr against resistant strain. Pyr and selected compounds (4n, 4p and 4t) that repressed parasite development also inhibited PfDHFR activity of the soluble parasite extract, suggesting that anti-parasitic activity of these compounds is a result of inhibition of the parasite DHFR. In silico studies suggest that activity of these compounds might be enhanced due to π-π stacking.