Design,synthesis and biological evaluation of N-arylsulfonyl carbazoles as novel anticancer agents

In this work, a set of structurally diverse synthetic carbazoles was screened for their anticancer activities. According to structure–activity relationship studies, carbazoles with an N-substituted sulfonyl group exhibited better anticancer activity. Moreover, compound 8h was discovered to show the most potent anticancer effects on Capan-2 cells by inducing apoptosis and cell cycle arrest in G2/M phase. Finally, the in vivo study demonstrated that 8h prevented the tumor growth in PANC-1 and Capan-2 xenograft models without apparent toxicity.

In this work, a set of structurally diverse synthetic carbazoles was screened for their anticancer activities.     

1,2,3-Triazole-fused spirochromenes as potential anti-tubercular agents: synthesis and biological evaluation

A facile and convenient approach has been designed for the synthesis of novel prototypes that possess the advantage of the two pharmacophores of chromene and 1,2,3-triazole in a single molecular backbone, were evaluated against Mycobacterium tuberculosis H37Rv strain. The new analogues 1,2,3-triazole-fused spirochromenes were accomplished in four step synthetic strategy utilizing click chemistry ([3 + 2] Huisgen cycloaddition) in the ultimate step. The synthesized compounds were established based on the spectral data and X-ray crystal structure for 7a. Among the compounds tested against Mycobacterium tuberculosis H37Rv strain, some products exhibited potent antimycobacterial activity with minimum inhibitory concentration (MIC) values ranging from 1.56 to 6.25 μg mL⁻¹. Compounds exhibiting good in vitro potency in the MTB MIC assay were further examined for cytotoxicity in a RAW 264.7 cells. Compounds 7a, 7d, 7i (MIC: 1.56 μg mL⁻¹) and 7k, 7m (MIC: 3.125 μg mL⁻¹) exhibited promising hits.

A convenient synthesis of novel prototypes containing the two pharmacophores of chromene and 1,2,3-triazole in a single molecular backbone, were evaluated against Mycobacterium tuberculosis H37Rv strain.     

Synthesis,characterization and biological evaluation of dipicolylamine sulfonamide derivatized platinum complexes as potential anticancer agents

Three new Pt complexes, [PtCl₂(N(SO₂(2-nap))dpa)], [PtCl₂(N(SO₂(1-nap))dpa)] and [PtCl₂(N(SO₂pip)dpa)], containing a rare 8-membered ring were synthesized in good yield and high purity by utilizing the ligands N(SO₂(2-nap))dpa, N(SO₂(1-nap))dpa and N(SO₂pip)dpa, which contain a dipicolylamine moiety. Structural studies of all three complexes confirmed that the ligands are bound in a bidentate mode via Pt–N_(pyridyl) bonds forming a rare 8-membered ring. The intense fluorescence displayed by the ligands is quenched upon coordination to Pt. According to time dependent density functional theory (TDDFT) calculations, the key excitations of N(SO₂(2-nap))dpa and [PtCl₂(N(SO₂(1-nap))dpa)] involve the 2-nap-ligand-centered π → π* excitations. While all six compounds have shown antiproliferative activity against human breast cancer cells (MCF-7), the N(SO₂pip)dpa and N(SO₂(2-nap))dpa ligands and [PtCl₂((NSO₂pip)dpa)] complex have shown significantly high cytotoxicity, directing them to be further investigated as potential anti-cancer drug leads.

Three new Pt complexes, [PtCl₂(N(SO₂(2-nap))dpa)], [PtCl₂(N(SO₂(1-nap))dpa)] and [PtCl₂(N(SO₂pip)dpa)], containing a rare 8-membered ring were synthesized in good yield and high purity by utilizing ligands which contain a dipicolylamine moiety.     

Triarylethylene-indolin-2,3-dione molecular conjugates: design,synthesis, docking studies and anti-proliferation evaluation

A series of 1H-1,2,3-triazole-linked ospemifene-isatin and O-methylated ospemifene–isatin conjugates were synthesized and assayed for their anti-proliferative activities against estrogen-responsive as well as estrogen-non-responsive cells. The non-cytotoxic conjugate 14e, with an optimal combination of bromo substituents at the C-5/C-7 positions of isatin, proved to be a promising hit with an IC₅₀ value of 31.62 μM against MCF-7 and 19.23 μM against MDA-MB-231. The observed anti-proliferative activities of active conjugates were further corroborated via docking studies carried out on estrogen receptor subtypes α and β.

A series of 1H-1,2,3-triazole-linked ospemifene–isatin and O-methylated ospemifene–isatin conjugates were synthesized and assayed for their anti-proliferative activities against estrogen-responsive as well as estrogen-non-responsive cells.     

Synthesis and evaluation of new chalcones and oximes as anticancer agents

Complex illnesses, such as cancer, are often caused by many disorders, gene mutations, or pathways. Biological pathways play a significant part in the development of these diseases. Multi-target directed ligands (MTDLs) have been used by medicinal chemists recently in an effort to find single molecules that can affect many targets concurrently. In this work, several chalcones containing the ligustrazine moiety were synthesized and tested for their in vitro anticancer activity and several cancer markers, including EGFR, BRAF^V600E, c-Met, and tubulin polymerization, in order to uncover multitarget bioactive compounds. In assays using multiple cancer cell lines, the majority of the compounds examined showed strong anticancer activity against them. To synthesize oximes, all of the chalcones were used as precursors. The IC₅₀ values of two compounds (11g and 11e) were found to be 0.87, 0.28, 2.43, 1.04 μM and 11d, 1.47, 0.79, 3.8, 1.63 μM respectively, against A-375, MCF-7, HT-29 and H-460 cell lines. These IC₅₀ values revealed an excellent antiproliferative activity compared to those of the positive control foretinib, (IC₅₀ = 1.9, 1.15, 3.97, and 2.86 μM). Careful examination of their structure and configuration revealed that both compounds had an oxime functional group with z configuration, in place of carbonyl functional group, along with a 2-phenyl thiophenyl moiety with or without a bromo group at position-5. The possible binding pattern was implied by docking simulation, inferring the possibility of introducing interactions with the nearby tubulin chain. Since the novel structural trial has been conducted with a detailed structure activity relationship discussion, this work might stimulate new ideas in further modification of multitarget anti-cancer agents and therapeutic approaches.

Discovery of multitarget anticancer agents by modifications of natural compound.     

Amino acid ester-coupled caffeoylquinic acid derivatives as potential hypolipidemic agents: synthesis and biological evaluation

Pandanus tectorius (L.) Parkins. (PTPs) is rich in caffeoylquinic acids and amino acids, especially some essential amino acids, such as valine, phenylalanine, and so forth. A series of novel amino acid ester-coupled caffeoylquinic acid derivatives have been designed and synthesized. Biological evaluation suggested that some amino acid ester-coupled derivatives exhibited varying degrees of lipid-lowering effects on oleic acid-elicited lipid accumulation in HepG2 liver cells. Particularly, derivatives 6c, 6d, 6e and 6f exhibited comparable potential lipid-lowering effect with the positive control simvastatin and chlorogenic acid. Further studies on the mechanism of 6c, 6d, 6e and 6f revealed that the lipid-lowering effects were related to their regulation of TG levels and mRNA levels of lipometabolic-modulating genes, and merit further investigation.

Amino acid ester-coupled caffeoylquinic acid derivatives as potential hypolipidemic agents.     

Design,synthesis and biological evaluation of 2-quinolyl-1,3-tropolone derivatives as new anti-cancer agents

Tropolones are promising organic compounds that can have important biologic effects. We developed a series of new 2-quinolyl-1,3-tropolones derivatives that were prepared by the acid-catalyzed reaction of 4,7-dichloro-2-methylquinolines with 1,2-benzoquinones. 2-Quinolyl-1,3-tropolones have been synthesized and tested for their anti-proliferative activity against several human cancer cell lines. Two compounds (3d and mixture B of 3i–k) showed excellent activity against six cancer cell lines of different tissue of origin. The promising compounds 3d and mixture B of 3i–k also demonstrated induction of apoptotic cell death of ovarian cancer (OVCAR-3, OVCAR-8) and colon cancer (HCT 116) cell lines and affected ERK signaling. In summary, 2-quinolyl-1,3-tropolones are promising compounds for development of effective anticancer agents.

Tropolones are promising organic compounds that can have important biologic effects.     

Synthesis,biological evaluation,and in silico studies of novel chalcone- and pyrazoline-based 1,3,5-triazines as potential anticancer agents

A novel series of triazin-chalcones (7,8)a–g and triazin-N-(3,5-dichlorophenyl)pyrazolines (9,10)a–g were synthesized and evaluated for their anticancer activity against nine different cancer strains. Triazine ketones 5 and 6 were synthesized from the cyanuric chloride 1 by using stepwise nucleophilic substitution of the chlorine atom. These ketones were subsequently subjected to a Claisen–Schmidt condensation reaction with aromatic aldehydes affording chalcones (7,8)a–g. Then, N-(3,5-dichlorophenyl)pyrazolines (9,10)a–g were obtained by cyclocondensation reactions of the respective chalcones (7,8)a–g with 3,5-dichlorophenylhydrazine. Among all the evaluated compounds, chalcones 7d,g and 8g exhibited more potent in vitro anticancer activity, with outstanding GI₅₀ values ranging from 0.422 to 14.9 μM and LC₅₀ values ranging from 5.08 μM to >100 μM. In silico studies, for both ligand- and structure-based, were executed to explore the inhibitory nature of chalcones and triazine derivatives. The results suggested that the evaluated compounds could act as modulators of the human thymidylate synthase enzyme.

A novel series of triazin-chalcones (7,8)a–g and triazin-N-(3,5-dichlorophenyl)pyrazolines (9,10)a–g were synthesized and evaluated for their anticancer activity against nine different cancer strains.     

Synthesis and biological evaluation of indazole derivatives as anti-cancer agents

Several FDA approved small molecule anti-cancer drugs contain indazole scaffolds. Here, we report the design, synthesis and biological evaluation of a series of indazole derivatives. In vitro antiproliferative activity screening showed that compound 2f had potent growth inhibitory activity against several cancer cell lines (IC₅₀ = 0.23–1.15 μM). Treatment of the breast cancer cell line 4T1 with 2f inhibited cell proliferation and colony formation. 2f dose-dependently promoted the apoptosis of 4T1 cells, which was connected with the upregulation of cleaved caspase-3 and Bax, and downregulation of Bcl-2. 2f also decreased the mitochondrial membrane potential and increased the levels of reactive oxygen species (ROS) in 4T1 cells. Additionally, treatment with 2f disrupted 4T1 cells migration and invasion, and the reduction of matrix metalloproteinase metalloproteinase-9 (MMP9) and increase of tissue inhibitor matrix metalloproteinase 2 (TIMP2) were also observed. Moreover, 2f could suppress the growth of the 4T1 tumor model without obvious side effects in vivo. Taken together, these results identified 2f as a potential small molecule anti-cancer agent.

One of the synthesized indazole derivatives, 2f, displayed inhibitory activities against proliferation, migration and invasion of breast cancer cell line 4T1, with the potential of inducing cell apoptosis, and suppressing tumor growth in vivo.     

Synthesis and biological evaluation of 4-(1H-1,2,4-triazol-1-yl)benzoic acid hybrids as anticancer agents

A series of 4-(1H-1,2,4-triazol-1-yl)benzoic acid hybrids (1–17) was successfully synthesized and their structures were established by NMR and MS analysis. In vitro cytotoxic evaluation indicated that some of the hybrids exhibited potent inhibitory activities against MCF-7 and HCT-116 cancer cell lines, with IC₅₀ values ranging from 15.6 to 23.9 µM, compared with reference drug doxorubicin (19.7 and 22.6 µM, respectively). Notably, the most potent compounds, 2, 5, 14, and 15, not only exhibited an obvious improvement in IC₅₀ values, but demonstrated very weak cytotoxic effects toward normal cells (RPE-1) compared with doxorubicin. A further investigation showed that compounds 2 and 14 clearly inhibited the proliferation of MCF-7 cancer cells by inducing apoptosis. In addition, these hybrids showed acceptable correlation with bioassay results in regression plots generated by 2D QSAR models. Our results indicated that 1,2,4-triazole benzoic acid hybrids could be used as a structural optimization platform for the design and development of more selective and potent anticancer molecules.

A series of 4-(1H-1,2,4-triazol-1-yl)benzoic acid hybrids (1–17) was successfully synthesized and their structures were established by NMR and MS analysis. Their anticancer activity against HCT-116, MCF-7 and normal human RPE-1 cells were examined.     

Design,synthesis, and biological evaluation of new 6,N2-diaryl-1,3,5-triazine-2,4-diamines as anticancer agents selectively targeting triple negative breast cancer cells

New 6,N²-diaryl-1,3,5-triazine-2,4-diamines were designed using the 3D-QSAR model developed earlier. These compounds were prepared and their antiproliferative activity was evaluated against three breast cancer cell lines (MDA-MB231, SKBR-3 and MCF-7) and non-cancerous MCF-10A epithelial breast cells. The synthesized compounds demonstrated selective antiproliferative activity against triple negative MDA-MB231 breast cancer cells. The most active compound in the series inhibited MDA-MB231 breast cancer cell growth with a GI₅₀ value of 1 nM. None of the tested compounds significantly affected the growth of the normal breast cells. The time-dependent cytotoxic effect, observed when cytotoxicity was assessed at different time intervals after the treatment, and morphological features, observed in the fluorescence microscopy and live cell imaging experiments, suggested apoptosis as the main pathway for the antiproliferative activity of these compounds against MDA-MB231 cells.

New highly potent and selective 6,N²-diaryl-1,3,5-triazine-2,4-diamines were designed and prepared using the 3D-QSAR model developed earlier.     

Folic acid-sulfonamide conjugates as antibacterial agents: design,synthesis and molecular docking studies

Dihydrofolate reductase (DHFR) inhibitors, as antibacterial agents, contain pyrimidine, pteridine, and azine moieties among many other scaffolds. Folic acid (FA), with a pteridine ring and amine group, was used as our focus scaffold, which was then conjugated with sulfonamides to develop new conjugates. The novel synthesized conjugates were characterized using infrared spectroscopy, and ¹H and ¹³C nuclear magnetic resonance (NMR) spectral studies and consequently screened for antimicrobial activities against bacterial strains with ampicillin as a positive control. Compound DS2 has the highest zone of inhibition (36.6 mm) with a percentage activity index (%AI) value of 122.8% against S. aureus and a minimum inhibitory concentration (MIC) of 15.63 μg mL⁻¹. DHFR enzyme inhibition was also evaluated using the synthesized conjugates through in vitro studies, and inhibition assays revealed that compound DS2 exhibited a 75.4 ± 0.12% (mean ± standard error of the mean (SEM)) inhibition, which is comparable with the standard DHFR inhibitor trimethoprim (74.6 ± 0.09%). The compounds attached to the unsubstituted aryl moiety of the sulfonamides revealed better inhibition against the bacterial strains as compared to the methyl substituted aryl sulfonamides. Molecular docking studies of the novel synthesized conjugates were also performed on the DHFR enzyme to identify the plausible binding modes to explore the binding mechanisms of these conjugates.

Dihydrofolate reductase (DHFR) inhibitors, as antibacterial agents, contain pyrimidine, pteridine, and azine moieties among many other scaffolds.     

Design,synthesis and bioevaluation of novel 6-substituted aminoindazole derivatives as anticancer agents

In the present study, a series of 6-substituted aminoindazole derivatives were designed, synthesized, and evaluated for bio-activities. The compounds were initially designed as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors based on the structural feature of five IDO1 inhibitors, which are currently on clinical trials, and the important anticancer activity of the indazole scaffold. One of them, compound N-(4-fluorobenzyl)-1,3-dimethyl-1H-indazol-6-amine (36), exhibited a potent anti-proliferative activity with an IC₅₀ value of 0.4 ± 0.3 μM in human colorectal cancer cells (HCT116). This compound also remarkably suppressed the IDO1 protein expression. In the cell-cycle studies, the suppressive activity of compound 36 in HCT116 cells was related to the G2/M cell cycle arrest. Altogether, the current findings demonstrate that compound 36 would be promising for further development as a potential anticancer agent.

In the present study, a series of 6-substituted aminoindazole derivatives were designed, synthesized, and evaluated for bio-activities.     

Synthesis and biological evaluation of dehydroabietic acid-pyrimidine hybrids as antitumor agents

A series of novel dehydroabietic acid derivatives containing pyrimidine moieties were designed and synthesized to explore more efficacious and less toxic antitumor agents according to the principle of combination and hybridization. The cytotoxicity against human liver cancer (HepG2) cells, human breast cancer (MCF-7) cells, human colon cancer (HCT-116) cells, human lung cancer (A549) cells, and human normal liver cells (LO2) was estimated by MTT assay in vitro. Cytotoxic activity screening revealed that most of the compounds showed moderate to high levels of cytotoxicity against these four cancer cell lines and that some displayed more potent inhibitory activities compared with 5-FU. In particular, compound 3b exhibited promising cytotoxicity with IC₅₀ values ranging from 7.00 to 11.93 μM against all the tested cell lines and displayed weak cytotoxicity towards normal cells. Besides, cell cycle analysis indicated that compound 3b mainly arrested MCF-7 cells at the S stage and induced cell apoptosis.

A series of novel dehydroabietic acid derivatives containing pyrimidine moieties were designed and synthesized. Some of them displayed more potent inhibitory activities compared with 5-FU.     

Platinum-based anticancer agents: innovative design strategies and biological perspectives

The impact of cisplatin on cancer chemotherapy cannot be denied. Over the past 20 years, much effort has been dedicated to discover new platinum-based anticancer agents that are superior to cisplatin or its analogue, carboplatin. Most structural modifications are based on changing one or both of the ligand types coordinated to platinum. Altering the leaving group can influence tissue and intracellular distribution of the drug, whereas the carrier ligand usually determines the structure of adducts formed with DNA. DNA-Pt adducts produced by cisplatin and many of its classical analogues are almost identical, and would explain their similar patterns of tumor sensitivity and susceptibility to resistance. Recently some highly innovative design strategies have emerged, aimed at overcoming platinum resistance and/or to introduce novel mechanisms of antitumor action. Platinum compounds bearing the 1,2-diaminocyclohexane carrier ligand; and those of multinuclear Pt complexes giving rise to radically different DNA-Pt adducts, have resulted in novel anticancer agents capable of circumventing cisplatin resistance. Other strategies have focused on integrating biologically active ligands with platinum moieties intended to selectively localizing the anticancer properties. With the rapid advance in molecular biology, combined with innovation, it is possible new Pt-based anticancer agents will materialize in the near future.     

Rigid 3D-spiro chromanone as a crux for efficient antimicrobial agents: synthesis,biological and computational evaluation

The development of new and effective antimicrobial agents with novel chemical skeletons and working mechanisms is highly desirable due to the increased number of resistant microbes. Different new compounds based upon a 3D-spiro chromanone scaffold such as Mannich bases 2 and 3 in addition to azo dye 4 were synthesized. Besides, the condensation reactions of the hydrazide-spiro chromanone 8 with different ketonic reagents led to the synthesis of pyrazoles (9 & 10) and anils (11 & 13). Moreover, the methoxyl substituted spiro chromanone 14 was condensed with different hydrazines and hydrazides to give the corresponding hydrazones 15–18 in up to 85% yields. The condensation of the hydrazone 18 with salicylaldehyde yielded coumarinyl spiro chromanone 19 in an excellent yield, whereas its reaction with benzaldehyde followed by hydrazine afforded aminopyrazole derivative 21 in 82% yield. The antimicrobial evaluation suggested that hydrazide 8 has a substantial activity against different microbes (S. aureus: D = 22 mm, MIC = 1.64 μM; E. coli: D = 19 mm, MIC = 1.64 μM; C. albicans: D = 20 mm, MIC = 6.57 μM). Moreover, promising antimicrobial activities were observed for azo dye 4 (D = 13–19 mm, MIC = 5.95–11.89 μM), hydrazone 17 (D = 17–23 mm, MIC = 1.88–3.75 μM), and aminopyrazole 21 (D = 14–19 mm, MIC = 2.24–8.98 μM). The molecular docking revealed that compounds 4, 8, 17, and 21 had good to high binding affinities with different microbial targets such as penicillin-binding proteins (−7.4 to −9.9 kcal), DNA gyrase (−7.8 to −9.0 kcal), lanosterol 14-alpha demethylase (−8.2 to −11.2 kcal), and exo-beta-1,3-glucanase (−8.2 to −11.9 kcal). The QSAR analysis ascertained a good correlation between the antimicrobial activity of 3D-spiro chromanone derivatives and their structural and/or physicochemical parameters.

New heterocyclic compounds based upon rigid 3D-spiro chromanone scaffold have been synthesized and evaluated as efficient antimicrobial agents. Molecular docking and QSAR have explained and supported the observed promising antimicrobial activity.     

Photodegradable antimicrobial agents − synthesis,photodegradation, and biological evaluation

Multi-drug resistant (MDR) bacteria are already a significant health-care problem and are making the combat of infections quite challenging. Here we report the synthesis of several new compounds containing an ethanolamine moiety, of which two exhibit promising antimicrobial activity (at the 6 μM level). All the compounds are degraded when exposed to light and form inactive products.

The synthesis of several new compounds containing an ethanolamine moiety are reported, of which two exhibit promising antimicrobial activity (at the 6 μM level).