Molecular modeling,synthesis, antibacterial and cytotoxicity evaluation of sulfonamide derivatives of benzimidazole,indazole, benzothiazole and thiazole

A new series of heterocyclic molecules bearing sulfonamide linkage has been synthesized and screened for antibacterial activity. During antibacterial screening using broath dilution method, molecules were found to be highly active (MIC value 50–3.1?µg/mL) against different human pathogens, namely B. cerus, S. aureus, E. coli and P. aeruginosa, and most effective against E. coli. A great synergistic effect was observed during determination of FIC where molecules were used in combination with reference drugs chloramphenicol and sulfamethoxazole. The MIC value of the combination – varying concentration of test compounds and ½ MIC of reference drugs or varying concentration of reference drugs and ½ MIC of test compounds, was reduced up to ¹/₄ or ¹/₃₂ of the original value, indicating thereby the combination was 4–32 times more potent than the test molecule. The molecules also showed low degree of cytotoxicity against PBM, CEM and VERO cell lines. The results positively indicated towards the development of lead antibacterials using the combination approach.     

Iodine-catalyzed conjugate addition of indoles onto en-1,4-dione: a novel synthesis of 3-(1-(1H-indol-3-yl)-2-oxo-2-phenylethyl)indolin-2-ones as antibacterial and antifungal agents

Indole and its derivatives undergo smooth conjugate addition onto en-1,4-dione derived from isatin and acetophenone, in the presence of a catalytic amount of molecular iodine in acetonitrile under mild conditions to afford a novel class of 3-(1-(1H-indol-3-yl)-2-oxo-2-phenylethyl)indolin-2-one derivatives in good yields with high degree of 1,4-selectivity. Some of these compounds are found to exhibit modest antibacterial and antifungal properties.     

New bithiazolyl hydrazones: Novel synthesis,characterization and antitubercular evaluation

New bithiazolyl hydrazones (6a–l) have been first time synthesized by carrying novel one pot cyclocondensation of 5-acyl thiazoles (1a–b), thiosemicarbazide (2) and substituted phenacyl chlorides (4a–f) in freshly prepared ionic liquid, diisopropyl ethyl ammonium acetate (DIPEAc) at room temperature. The newly synthesized compounds have been evaluated for their antitubercular activity and the compounds 3b, 6a, 6b, 6d, 6e, 6f, 6g, and 6l have displayed noticeable antitubercular activity compared to Rifampicin with tolerable cytotoxicity. All these compounds were also screened for their antibacterial activity and found that, compounds 6j and 6k have exhibited a very good antibacterial activity. Molecular docking study has shown better harmony with the evaluation trend shown by these compounds under in vitro antitubercular screening.     

Biogenic synthesis of silver nanoparticles: Antibacterial and cytotoxic potential

In green chemistry, the application of a biogenic material as a mediator in nanoparticles formation is an innovative nanotechnology. Our current investigation aimed at testing the cytotoxic potential and antimicrobial ability of silver nanoparticles (AgNPs) that were prepared using Calligonum comosum roots and Azadirachta indica leaf extracts as stabilizing and reducing agents. An agar well diffusion technique was employed to detect synthesized AgNPs antibacterial ability on Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus bacterial strains. Furthermore, their cytotoxic capability against LoVo, MDA-MB231 and HepG2 ca cells was investigated. For phyto-chemical detection in the biogenic AgNPs the Fourier-transform infrared spectroscopy (FT-IR) was considered. Zeta sizer, TEM (Transmission Electron Microscope) and FE-SEM (Field Emission Scanning Electron Microscope) were used to detect biogenic AgNPs’ size and morphology. The current results showed the capability of tested plant extract for conversion of Ag ions to AgNPs with a mean size ranging between 90.8 ± 0.8 and 183.2 ± 0.7 nm in diameter. Furthermore, prepared AgNPs exhibited apoptotic potential against HepG2, LoVo, and MDA-MB 231cell with IC₅₀ ranging between 10.9 and 21.4 μg/ml and antibacterial ability in the range of 16.0 ± 0.1 to 22.0 ± 1.8 mm diameter. Activation of caspases in AgNPs treated cells could be the main indicator for their positive effect causing apoptosis. The current investigation suggested that the green production of AgNPs could be a suitable substitute to large-scale production of AgNPs, since stable and active nanoparticles could be obtained.     

Design,synthesis and biological evaluation of novel indolin-2-ones as potent anticancer compounds

The indolin-2-one core is a privileged structure for antitumor agents, especially kinase inhibitors. Twenty-three novel indolin-2-ones were designed by molecular dissection of the anticancer drug indirubin. Seventeen of them exhibited significant inhibition against the tested cell lines, and two of them (1c and 1h) showed IC₅₀ values at the submicromolar level against HCT-116 cells. Compounds 1c and 2c were also potent inhibitors of the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometry was utilized to explore the antitumor mechanism of 1c and 2c with MDA-MB-231 cells, and distinct effects were observed on 2c. Furthermore, immunocytochemical examination of 1c suggested a destabilization of microtubules, which was significantly different from the effect of IM, an indirubin derivative.     

Rational design,molecular docking and synthesis of novel homopiperazine linked imidazo[1,2-a]pyrimidine derivatives as potent cytotoxic and antimicrobial agents

Designed and synthesized novel homopiperazine linked imidazo[1,2-a]pyrimidine derivatives (10a–i, 11a–g, 12), and evaluated them for their in vitro cytotoxicity against HeLa cells (cervical cancer), A549 cells (lung cancer) cells, by MTT assay. Compound 12 (IC₅₀ = 4.14 µM) and compound 10c (IC₅₀ = 5.98 µM) were found to be 2.5 fold, and 1.74 fold more potent when compared with standard Etoposide (IC₅₀ = 10.44 µM), against A549 (lung cancer cells). Compound 12 also found to be 1.57 and 1.13 fold potent against DU145 (IC₅₀ = 6.24 µM) and HeLa (IC₅₀ = 6.54 µM), respectively when compared with Etoposide (DU145, IC₅₀ = 9.8 µM; HeLa, IC₅₀ = 7.43 µM). Compound 10f (IC₅₀ = 6.12 µM) was found to be 1.31 fold more potent than Etoposide (IC₅₀ = 7.43 µM) against HeLa cell lines.Moreover compounds 10a and 11a showed cytotoxicity at low micro-molar concentrations against A549 cells. Synthesized compounds were also evaluated for their antimicrobial activity by Cup plate diffusion method. Compounds 10c, 11b, 11d and 11f displayed remarkable antimicrobial activity relating to their standard drugs Gentamycin, Amphotericin B and Ampicillin. Significantly, compound 10c showed broad spectrum activity against tested microbial strains. All the designed compounds were well occupied the binding site of the colchicine and interacted with both α- and β-tubuline interface (PDB ID: 3E22), which demonstrates that synthesized compounds are promising tubulin inhibitors. Also, the synthesized compounds occupied the catalytic triad and adenine-binding site, in the active site of β-ketoacyl-acyl carrier protein synthase III enzyme (PDB ID: 1MZS). The molecular docking results provided the useful information for the future design of more potent inhibitors. These preliminary results convinced further investigation and modifications on synthesized compounds aiming towards the development of potential cytotoxic as well as antimicrobial agents.     

Synthesis and preliminary evaluation of curcumin analogues as cytotoxic agents

A series of curcumin analogues with different substituents at the 4-position of the phenyl group were synthesized and screened for in vitro cytotoxicity against a panel of human cancer cell lines. Several novel curcumin analogues, especially 32 and 34, exhibited selective and potent cytotoxic activity against human epidermoid carcinoma cell line A-431 and human glioblastoma cell line U-251, implying their specific potential in the chemoprevention and chemotherapy of skin cancer and glioma. The preliminary SAR information extracted from the results suggested that introduction of appropriate substituents to the 4′-positions could be a promising approach for the development of new cytotoxic curcumin analogues with special selectivity for A-431 and U-251 cell lines.     

Facile synthesis of new 4-aza-podophyllotoxin analogs via microwave-assisted multi-component reactions and evaluation of their cytotoxic activity

A series of new 4-aza-podophyllotoxin analogs containing thiazole unit were synthesized via multi-component reactions of aldehydes, tetronic acid and 2-methylbenzo[d]thiazol-5-amine under microwave irradiation. The method not only provides a valuable tool in design and synthesis of new 4-aza-podophyllotoxin analogs but also has the advantages of atom-economy, environmental-friendliness, good yields and operational simplicity. More importantly, the preliminary evaluation on the cytotoxic activity of this type of new 4-aza-podophyllotoxin analogs has resulted in the finding of several compounds with potent and efficacious cytotoxicity to three carcinoma cell lines M14, MCF7 and SW1116.     

Design,synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities

A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a–5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC₅₀, 0.64 μM for AChE and 0.42 μM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver–Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a–5r) did not affect PC12 and HepG2 cell viability at the concentration of 10 μM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer’s disease.     

Design,synthesis and biological evaluation of 8-substituted-6-hydrazonoindolo[2,1-b]quinazolin-12(6H)-one scaffolds as potential cytotoxic agents: IDO-1 targeting molecular docking studies

Herein, we have reported the synthesis of 18 novel 8-substituted tryptanthrin analogues based on our earlier work. All these tryptanthrin analogues were well characterized by ¹H & ¹³C NMR, FT-IR, Mass Spectrometry and Elemental Analysis. All these 8-substituted analogues were screened for their anti-oxidant activity by DPPH radical scavenging assay. Out of all the tested compounds, T¹¹, T¹², T¹⁷ and T¹⁸ showed potent anti-oxidant activity. The anti-cancer activity have been performed by using MTT assay protocol and their results depicts that compounds having the 4-pyridyl or 4-carboxyphenyl substituents at the 8th position of the tryptanthrin framework are found to be the most promising cytotoxic agent against A549, MCF-7 and HeLa human cancer cell lines compared to others as well as with the standard drug cisplatin. Moreover, the comparative molecular docking studies against the three protein receptors IDO1, EGFR and HER2 strongly suggested that IDO1 is the best target protein, which exhibits lowest binding energies of ?11.73 and ?11.61 kcal mol^?1 for T¹¹ and T¹² scaffolds, respectively towards the in vitro anti-cancer activity.     

Synthesis and evaluation of pyrazolines bearing benzothiazole as anti-inflammatory agents

The present study aims at the synthesis of pyrazolines bearing benzothiazole and their evaluation as anti-inflammatory agents. The synthesized compounds were evaluated for their anti-inflammatory potential using carrageenan induced paw edema model. Two compounds 5a and 5d alleviated inflammation more than the standard drug celecoxib. Eight compounds 5b, 5c, 5e, 5g, 5h, 6b, 6e and 6f showed anti-inflammatory activity comparable to celecoxib. To understand the mode of action, COX-2 enzyme assay and TNF-α assay were carried out. All the active compounds were assessed for their cytotoxicity. The ulcerogenic risk evaluation was performed on the active compounds that were not found to be cytotoxic. Out of ten active compounds, two compounds (5d and 6f) were finally found to be the most potent anti-inflammatory agents attributing to the suppression of the COX-2 enzyme activity and TNF-α production without being either cytotoxic or ulcerogenic.     

Synthesis and biological evaluation of amino analogs of Ludartin: Potent and selective cytotoxic agents

Diverse amino analogs of Ludartin, a cytotoxic guaianolide and a position isomer of an anticancer drug, Arglabin were prepared through Michael type addition at its highly active α-methylene-γ-lactone motif. The semisynthetic derivatives were subjected to sulphorhodamine B cytotoxicity assay against a panel of four different human cancer cell lines viz. lung (A-549), leukemia (THP-1), prostate (PC-3) and colon (HCT-116) to look into structure–activity relationship. Few of the analogs displayed potent selective cytotoxicity compared to the parent molecule-Ludartin (1). (11R)-13-(Diethyl amine)-11,13-dihydroludartin (6) and (11R)-13-(piperidine)-11,13-dihydroludartin (10) showed almost same cytotoxicity against leukemia cell lines (THP-1) as that of parent molecule-Ludartin, but were more active against colon (HCT-116) cancer cells. (11R)-13-(Morpholine)-11,13-dihydroludartin (11) displayed selectively better cytotoxicity against Leukemia cancer cells (THP-1) exhibiting IC₅₀ of 2.8 μM. (11R)-13-(6-Nitroindazole)-11,13-dihydroludartin (17) was four times more potent than Ludartin with selective cytotoxic effects against prostate cancer cells (2.2 μM) while as (11R)-13-(6-nitroindazole)-11,13-dihydroludartin (18) exhibited three-fold selective cytotoxicity for Lung (A-549) cancer cell lines exhibiting IC₅₀ of 2.6 μM.     

ent-Kaurane diterpenes from the stem bark of Annona vepretorum (Annonaceae) and cytotoxic evaluation

This work describes a novel ent-kaurane diterpene, ent-3β-hydroxy-kaur-16-en-19-al along with five known ent-kaurane diterpenes, ent-3β,19-dihydroxy-kaur-16-eno, ent-3β-hydroxy-kaur-16-eno, ent-3β-acetoxy-kaur-16-eno, ent-3β-hydroxy-kaurenoic acid and kaurenoic acid, as well as caryophyllene oxide, humulene epoxide II, β-sitosterol, stigmasterol and campesterol from the stem bark of Annona vepretorum Mart. (Annonaceae). Cytotoxic activities towards tumor B16-F10, HepG2, K562 and HL60 and non-tumor PBMC cell lines were evaluated for ent-kaurane diterpenes. Among them, ent-3β-hydroxy-kaur-16-en-19-al was the most active compound with higher cytotoxic effect over K562 cell line (IC₅₀ of 2.49 μg/mL) and lower over B16-F10 cell line (IC₅₀ of 21.02 μg/mL).     

Diterpenoids from the stems of Tripterygium hypoglaucum (Celastraceae) and cytotoxic evaluation

Four new diterpenoids, 2α,16α-hydroxy-ent-kauran-19,20-olide (1), isopimara-8(14),15-diene-11β,19-diol (2), isopimara-8(14),15-diene-12α,19-diol (3), and 3-oxo-14,15-dihydroxyabieta-8,11,13-trien-19-ol (4), along with seven known compounds (5–11) were isolated from Tripterygium hypoglaucum. Their structures were established on the basis of extensive spectroscopic analysis. Triptolide (5) and 2-epitripdiolide (6) showed significant cytotoxicity against A549, DU145, KB, KBvin and MDA-MB-231 cell lines with IC₅₀ values of 0.0012–0.1306 μM in vitro.     

One-pot synthesis of cinnamylideneacetophenones and their in vitro cytotoxicity in breast cancer cells

A series of cinnamylideneacetophenones were synthesized via a modified Claisen–Schmidt condensation reaction and evaluated for cytotoxicity against breast cancer cells using the Alamar Blue™ assay. Derivatives 17 and 18 bearing a 2-nitro group on the B ring, exhibited sub-micromolar cytotoxicity in MCF-7 cells (IC₅₀ = 71 and 1.9 nM), respectively. Derivative 17 also displayed sub-micromolar (IC₅₀ = 780 nM) cytotoxicity in MDA-MB-468 cells. Additionally, 17 and 18 displayed significantly less cytotoxicity than the chemotherapeutic doxorubicin in non-tumorigenic MCF-10A cells. This study provides evidence supporting the continued development of nitro-substituted cinnamylideneacetophenones as small molecules to treat breast cancer.     

Poly-guanidinoethylphenylethers organised around a benzene ring: Synthesis and evaluation of their antibacterial and cytotoxic properties

A new family of poly-guanidinium species with a benzene core as the organising agent has been developed. Their antibacterial properties have been evaluated against reference Gram positive and Gram negative bacteria, and their cytotoxicity against eukaryotic cells. Most of these compounds exhibited Minimum Inhibitory Concentrations in the micromolar range.     

Design and synthesis of 1,2,3-triazolo-phenanthrene hybrids as cytotoxic agents

A series of new 1,2,3-triazolo-phenanthrene hybrids has been synthesized by employing Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. These compounds were evaluated for their in vitro cytotoxic potential against various human cancer cell lines viz. lung (A549), prostate (PC-3 and DU145), gastric (HGC-27), cervical (HeLa), triple negative breast (MDA-MB-231, MDA-MB-453) and breast (BT-549, 4T1) cells. Among the tested compounds, 7d displayed highest cytotoxicity against DU145 cells with IC₅₀ value of 1.5 ± 0.09 µM. Further, the cell cycle analysis shown that it blocks G0/G1 phase of the cell cycle in a dose dependent manner. In order to determine the effect of compound on cell viability, phase contrast microscopy, AO/EB, DAPI, DCFDA and JC-1 staining studies were performed. These studies clearly indicated that the compound 7d inhibited the cell proliferation of DU145 cells. Relative viscosity measurements and molecular docking studies indicated that these compounds bind to DNA by intercalation.     

Essential oil composition of Senecio graciliflorus DC: Comparative analysis of different parts and evaluation of antioxidant and cytotoxic activities

The essential oil of different parts of Senecio graciliflorus DC was obtained by hydrodistillation and analysed by GC-FID and GC–MS for the first time. A total of 17, 20, 19 and 17 constituents were identified comprising 99.90, 95.50, 98.93 and 95.96% of the essential oil of flower, leaf, stem and root parts of Senecio graciliflorus respectively. Monoterpene hydrocarbons predominated in the essential oil with 85.28% in flower, 57.53% in leaf, 67.74% in stem and 64.98% in root oil. α-pinene, cis-ocimene, 1,2,3-trimethylcyclohexane and β-pinene were the major constituents of the essential oil. The flower essential oil exhibited a strong antioxidant potential displaying IC₅₀ values of 21.6 ± 0.6 and 26.0 ± 1.0 μg/ml in DPPH and hydroxyl radical assays respectively. On the other hand the essential oil of flower and root displayed highest cytotoxicity against lung (A-549) cancer cell lines (IC₅₀ = 19.1 ± 0.9 and 21.3 ± 1.1 μg/ml respectively. This study which represents the first report of the essential oil composition and bioevaluation of Senecio graciliflorus, can serve as a new source of cytotoxic and antioxidant activity.     

Macrocyclic biphenyl tetraoxazoles: Synthesis,evaluation as G-quadruplex stabilizers and cytotoxic activity

A series of macrocyclic biphenyl tetraoxazoles was synthesized. The latter stages of the synthetic approach allowed for the addition of varied N-protected α-amino acids, which were subsequently deprotected and condensed to provide the desired macrocycles. Improved yields could be realized in the macrocyclization step of their synthesis relative to other macrocyclic G-quadruplex stabilizers. These 24-membered macrocycles were evaluated for their ability to stabilize G-quadruplex DNA and for their relative cytotoxicity against human tumor cells. These biphenyl tetraoxazoles were not strong ligands for G-quadruplex DNA relative to other macrocyclic polyoxazoles. This reduced stabilizing potential did correlate with their comparatively lower cytotoxic activity as observed in the human tumor cell lines, RPMI 8402 and KB3-1. These studies provide useful insights into the conformational requirements for the development of selective and more potent G-quadruplex ligands.     

Synthesis and biological evaluation of new 1,5-diazaanthraquinones with cytotoxic activity

A series of 1,5-diazaanthraquinone derivatives was synthesized and their in vitro cytotoxic activities were evaluated against several human cancer cell lines. The 1,5-diazaanthraquinone chromophore has been synthesized either on the basis of hetero Diels–Alder reactions involving different quinoline-5,8-diones and ,β-unsaturated aldehyde N,N-dimethylhydrazones or by thermolysis of different arylaminomethylene Meldrum’s acid derivatives. Some of these compounds showed cytotoxic activity comparable to that of mitoxantrone against most of the cell lines tested. Compounds 20, 30, 31 and 37 were 4–54 times more potent that mitoxantrone against A549, H116, PSN1 and T98G cancer cell lines but, interestingly, they were 3–16 times less potent against the human breast carcinoma SKBR3. Some structure–activity relationships are described, the most significant one being the increase in cytotoxicity resulting from the introduction of a halogen atom at the C-4 position.