Design, Synthesis, Anticancer Evaluation, and Molecular Docking Studies of Novel Benzoxazole Linked 1,3,4-Oxadiazoles.

BACKGROUND: Cancer disease is a serious concern globally. Global cancer occurrence is steadily increasing every year. There is always a persistent need to develop new anticancer drugs with reduced side effects or that act synergistically with the existing chemotherapeutics. OBJECTIVE: Benzoxazoles are fused bicyclic nitrogen and oxygen-containing heterocyclic compounds and are considered biologically privileged scaffolds. We designed a synthetic route to link the benzoxazoles with oxadiazole,s resulting in a better pharmacophore for anticancer activity. METHODS: A series of novel amide derivatives of benzoxazole linked 1,3,4-oxadiazoles (10 a-j) were synthesized and characterized by 1H NMR, 13C NMR, and mass spectroscopic techniques. The biological properties of the compounds were screened in vitro against four different tumor cell lines. RESULTS: The results suggest that the compound 10b having 3,4,5-trimethoxy substitution on the phenyl ring exhibited potent anticancer activity in three cell lines (A549 = 0.13 ± 0.014 µM, MCF-7 = 0.10 ± 0.013 µM and HT-29 = 0.22 ± 0.017 µM). Notably, among the synthesized derivatives, compounds 10b, 10c, 10f, 10g, and 10i exhibited potent anticancer activity than the control, with IC50 values in the range from 0.11 ± 0.02 to 0.93 ± 0.034 µM. Molecular docking simulation results showed that compounds were stabilized by hydrogen bond and π-π interactions with the protein. CONCLUSION: The molecules showed comparable binding affinities with standard Combretastatin-A4. The present research work is in a preliminary phase and needs further studies to take the synthesized compounds to the next level in the cancer research field.

Selective CDK4/6 inhibition of novel 1,2,3-triazole tethered acridinedione derivatives induces G1/S cell cycle transition arrest via Rb phosphorylation blockade in breast cancer models.

CDK4 & CDK6 are essential regulators of initial cell cycle phases and are always considered an exciting choice for anti-cancer therapy. In the present study, we presented the structure-based rational design & synthesis of a new class of 1,2,3-triazole tethered acridinedione derivatives (6a-l) as selective CDK4/6 inhibitors. Title molecules were prepared as a result of the rate-determining reaction between substituted derivatives of 1-Phenyl-1H-1,2,3-triazole-4-carbaldehydes and substituted dimedones, and the molecules were structurally characterized by IR, 1H,13C NMR, and MS spectral data. All molecules were screened for in-vitro cytotoxic potential against a group of human breast tumor cell lines of distinct origin with differential Rb expression status. Out of entire series of conjugated hexahydro acridinediones, 6g showed potent cytotoxic effect against MCF-7, BT-474, and SK-BR3 cell lines with IC50values 0.173 ±â€¯0.037, 0.117 ±â€¯0.025, and 0.136 ±â€¯0.027 µM, respectively. Further, CDK inhibition assays revealed that the compounds 6g and 6h selectively inhibit CDK4/6 over other CDK-parter complexes of the family against the selected cell line group except for MDA-MB468 cells. Furthermore, apoptotic evaluation and cell cycle analysis determined that compound 6g successfully triggered apoptosis in all examined cell lines except MDA-MB468 through blocking G1/S cell cycle transformation. In addition, compound 6g showed the highest in-vitro selectivity towards CDK4/6 inhibition, even compared with Abemaciclib, and it was also proved for favourable in-vivo pharmacokinetic properties in male albino mice. Furthermore, molecule 6g showed promising tumor growth suppression with lower adverse effects in MCF-7 xenograft mice models, which could competently be considered as a novel chemotherapeutic candidate for a further comprehensive preclinical study involving breast cancer therapy.

Design and synthesis of novel (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones: a potential cytotoxic scaffolds and their molecular modeling studies.

In an effort to discover potential cytotoxic agents, a series of novel (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione derivatives (8a-n) were designed and synthesized in various steps with acceptable reaction procedures with quantitative yields and characterized by 1H NMR, 13C NMR, IR, HRMS and ESI-MS spectra. These newly synthesized novel derivatives were screened for their in vitro cell viability/cytotoxic studies against human breast cancer cell line (MCF-7) with various concentrations of 0.625 µM, 1.25 µM, 2.5 µM, 5 µM and 10 µM, respectively. The biological interpretation assay outcome was demonstrated in terms of cell viability percentage reduction and IC50 values against standard reference drug cisplatin. Based on these results, most of the derivatives exhibited promising cytotoxic activity. Among them, particularly compounds 8j (R1 = OMe and R3 = NO2) and 8e (R3 = CF3) demonstrate remarkable cytotoxic activity with IC50 values 0.426 µM ± 0.455 and 0.608 µM ± 0.408, which are even better than the standard drug cisplatin 0.636 µM ± 0.458 and compounds 8m (R2 = OMe and R3 = OMe) and 8c (R3 = OMe) exhibited closely equivalent IC50 values to the standard drug with IC50 values 0.95 µM ± 0.32 and 0.976 µM ± 0.313 and rest of the compounds exhibits moderate cytotoxic activity. Moreover, molecular modeling studies and ADME calculations of the novel synthesized derivatives are in adequate consent with the pharmacological screening results.

Synthesis, anti-diabetic evaluation and molecular docking studies of 4-(1-aryl-1H-1, 2, 3-triazol-4-yl)-1,4-dihydropyridine derivatives as novel 11-ß hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibitors.

11-Beta-Hydroxysteroid dehydrogenase-1(11ß-HSD1) inhibitors are one of the emerging classes of molecules to fight against diabetic complications. A novel series of 4-(1-substituted-1H-1,2,3-triazol-4-yl)-1,4-dihydropyridine derivatives were synthesized and evaluated for their anti-diabetic activity. Two compounds showed anti-diabetic activity very effectively. To clarify the mechanism of action of these compounds, the most potent compounds (5g and 5h) of the synthesized analogs were further studied by testing its 11-Beta Hydroxysteroid dehydrogenase-1 inhibitory activity through in vitro enzymatic experiments. The results showed that the 11ß-HSD1 inhibitory activity of compounds 5g and 5h was stable and efficient. Molecular docking studies revealed compounds 5g (-9.758) and 5h (-8.495) to have a stable binding patterns to the human 11-Beta-Hydroxysteroid dehydrogenase-1.

Synthesis, potentiometric and antimicrobial studies on metal complexes of isoxazole Schiff bases.

The metal complexes of Cu(II), Ni(II) and Co(II) with Schiff bases of 3-(2-hydroxy-3-ethoxybenzylideneamino)-5-methyl isoxazole [HEBMI] and 3-(2-hydroxy-5-nitrobenzylidene amino)-5-methyl isoxazole [HNBMI] which were obtained by the condensation of 3-amino-5-methyl isoxazole with substituted salicylaldehydes have been synthesized. Schiff bases and their complexes have been characterized on the basis of elemental analysis, magnetic moments, molar conductivity, thermal analysis and spectral (IR, UV, NMR and Mass) studies. The spectral data show that these ligands act in a monovalent bidentate fashion, co-ordinating through phenolic oxygen and azomethine nitrogen atoms. Chelates of Co(II), Ni(II) appear to be octahedral and Cu(II) appears to be distorted octahedral. To investigate the relationship between formation constants of binary complexes and antimicrobial activity, the dissociation constants of Schiff bases and stability constants of their binary metal complexes have been determined potentiometrically in aqueous solution at 30+/-1 degrees C and at 0.1 M KNO3 ionic strength and discussed. Antimicrobial activities of the Schiff bases and their complexes were screened. The structure-activity correlation in Schiff bases and their metal(II) complexes are discussed, based on the effect of their stability constants. It is observed that the activity enhances upon complexation and the order of activity is in accordance with stability order of metal ions.