Bioinspired thiazolo-[2,3-b] quinazolin-6-one derivatives as potent anti-cancer agents targeting EGFR: their biological evaluations and in silico assessment.

Cancer is a challenging and second most deadly disease. The epidermal growth factor receptors (EGFRs) dimerize upon ligand bindings to the extracellular domain that intiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphrylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. In this study, we unravel the binding mechanism of newly synthesized thiazolo-[2,3-b] quinazolin-6-one and evaluate their anti-cancer activity against ovary and prostate carcinoma cell lines (OVCAR-3 and PC-3). Synthesized molecules exhibited promising anti-cancer activity against OVCAR-3 and PC-3 carcinoma cell lines with inhibitory concentrations ranging from 13.4 ± 0.43 to 23.6 ± 1.22 µM and 7.5 ± 0.62 to 67.5 ± 1.24 µM, respectively. These compounds induced apoptosis and resulted in cell cycle arrest at G1 and G2/M transition phases. Next, the nude mice models were taken to investigate the toxicity of the 4bi compound, and in vivo investigations revealed no effects upon examined organs (liver and kidney) treated at different concentrations. Moreover, the combined in silico approaches, molecular docking, molecular dynamics simulations, and MM/PBSA methods were performed to assess the binding affinity and stability of bioinspired synthesized congeners with the epidermal growth factor receptor tyrosine kinase (EGFR-TK). The free binding energy (ΔGbind) of the 4bi molecule was found comparable to Erlotinib drug. The test molecule could be competent for further usage to determine its efficicacy in cancer therapeutics.

In Silico and In Vitro Evaluations of Fluorophoric Thiazolo-[2,3-b]quinazolinones as Anti-cancer Agents Targeting EGFR-TKD.

Epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) plays a pivotal role in cellular signaling, growth, and metabolism. The EGFR-TKD is highly expressed in cancer cells and was endorsed as a therapeutic target for cancer management to overcome metastasis, cell proliferation, and angiogenesis. The novel thiazolo-[2,3-b]quinazolinones series were strategically developed by microwave-assisted organic synthesis and multi dominos reactions aimed to identify the potent thiazolo-[2,3-b]quinazolinone inhibitor against EGFR-TKD. This study explores the binding stability and binding strength of newly developed series via molecular docking, molecular dynamics simulation, and MM/PBSA and MM/GBSA calculations. The binding interaction was observed to be through the functional groups on aryl substituents at positions 3 and 5 of the thiazolo-[2, 3-b]quinazolinone scaffold. The methyl substituents at position 8 of the ligands had prominent hydrophobic interactions corroborating their bindings similar to the reference FDA-approved drug erlotinib in the active site. ADMET predictions reveal that derivatives 5ab, 5aq, and 5bq are drug-like and may be effective in in vitro study. Molecular dynamics simulation for 100 ns of docked complexes revealed their stability at the atomistic level. The ΔGbinding of thiazolo-[2,3-b]quinazolinone was found to be 5ab - 22.45, 5aq - 22.23, and 5bq - 20.76 similar to standard drug, and erlotinib - 24.11 kcal/mol was determined by MM/GBSA method. Furthermore, the anti-proliferative activity of leads of thiazolo-[2,3-b]quinazolinones (n = 3) was studied against breast cancer cell line (MCF-7) and non-small lung carcinoma cell line (H-1299). The highest inhibitions in cell proliferation were shown by 5bq derivatives, and the IC50 was found to be 6.5 ± 0.67 µM against MCF-7 and 14.8 µM against H-1299. The noscapine was also taken as a positive control and showed IC50 at higher concentrations 37 ± 1 against MCF-7 and 46.5 ± 1.2 against H-1299.

A new class of fluorogenic thiazolo[2,3-b]quinazolinone receptor: selective detection towards mercury and hydrogen bisulfate ions in aqueous medium.

A series of fluorophoric and structurally diverse thiazoloquinazoline derivatives were synthesized in a one-pot multicomponent cascade reaction using a microwave irradiation technique. The unique structural arrangement of the synthesized compounds encouraged us to design a new type of bioactive molecular receptor. This receptor interacts with HSO4 - in 1 : 1 and Hg2+ in 1 : 2 binding stoichiometric ratios resulting in a change in fluorescence as well as absorption spectra in aqueous medium. The ion bonded receptor complex possibly enhances the fluorescence signal of the receptor via H-bonded complex formation with HSO4 - ions and co-ordinate complex formation with Hg2+ ions.

Resonance assignments and secondary structure prediction of secretory protein Rv0603 from Mycobacterium tuberculosis H37Rv.

We report the NMR resonance assignments of N-terminal signal sequence deleted secretory protein Rv0603 (∆1-28-Rv0603) from Mycobacterium tuberculosis H37Rv. ∆1-28-Rv0603 displayed good peak yield and signal dispersion in 2D [15N-1H] HSQC spectrum, which prompted us to proceed for resonance assignments on this construct. Standard triple-resonance experiments for resonance assignments were recorded on [U-15N]-∆Rv0603 and [U-15N, 13C]-∆Rv0603 samples. We obtained 97% of backbone 1HN, 98% of 13Cα, 98% of 1Hα, 96% of 13C´, 100% of 13Cß, 100% of 1Hß and 98% of side-chain 1H chemical shifts. This protein does not show any sequence similarity to any other protein of known structure. Determination of its solution structure would facilitate understanding of its biological function.

The construction of fluorophoric thiazolo-[2,3-b]quinazolinone derivatives: a multicomponent domino synthetic approach.

Acid-mediated one-pot domino reactions of substituted 2-amino thiazoles, substituted benzaldehydes and cyclic diketones have been developed for the synthesis of novel and architecturally unique thiazolo[2,3-b]quinazolinone derivatives under microwave irradiation. In this protocol, a series of thiazolo[2,3-b]quinazolinone derivatives have been synthesized and the excellent fluorescence behaviors of some of the molecules have been reported based on the incorporation of different electron-donating and electron-withdrawing substituents on the aryl moieties of the target molecules.

Growth-arresting Activity of Acmella Essential Oil and its Isolated Component D-Limonene (1, 8 P-Mentha Diene) against Trichophyton rubrum (Microbial Type Culture Collection 296).

BACKGROUND: Spilanthes acmella is used as a remedy in toothache complaints by the tribal people of Western part of Odisha, India. OBJECTIVE: The objective of this study was to study the growth-arresting activity of an indigenous Acmella essential oil (EO) (S. acmella Murr, Asteraceae) and its isolated component, d-limonene against Trichophyton rubrum (microbial type culture collection 296). MATERIALS AND METHODS: The EO was extracted from flowers of indigenous S. acmella using Clevenger's apparatus and analyzed by gas chromatography-mass spectrometry (GC-MS). High pressure liquid chromatography (HPLC) was carried out to isolate the major constituent. The isolated fraction was subjected to fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). The antidermatophytic activity was screened for using "disc diffusion" and "slant dilution" method followed by optical, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) studies. The molecular dockings were made between d-limonene with cell wall synthesis-related key enzymes (14 methyl deaminase and monooxygenase). RESULTS: The GC-MS analysis EO had inferred the presence of 7 number of major (≥2%) components. The component with highest peak area (%) was found to be 41.02. The HPLC-isolated fraction was identified as d-limonene (1,8 p-Mentha-diene) by FTIR and NMR. Qualitative and quantitative assays had suggested the growth inhibitory activity of Acmella EO and its component. Shrinkage, evacuation, cell wall puncture, and leakage of cellular constituents by the activity of Acmella oil and d-limonene were evidenced from optical, SEM, and TEM studies. The computer simulation had predicted the binding strengths of d-limonene and fluconazole with dermatophyte cell wall enzymes. CONCLUSION: There could have been synergistic action of all or some of compounds present in indigenous Acmella EO. SUMMARY: There was presence of seven number of (d-limonene, ocimene, ß-myrcene, cyclohexene, 3-(1, 5-dimethyl-4-hexenyl)-6-methylene, ß-caryophyllene, and ß-sesquiphellandrene and ß-phellandrene) major components in the indigenous Acmella essential oilThe d-limonene content was 41.02% in the indigenous oilThe antidermatophytic activity of Acmella essential oil could have been attributable to its chemotypes. Abbreviations used: °C: Degree centigrade; w/v: Weight/volume; TS: Transverse section; min: minute; Hz: hertz: h: Hr.

Design, synthesis and cytotoxicity of novel chalcone analogs derived from 1-cyclohexylpyrrolidin-2-one and 2,3-dihydrobenzo[f]chromen-1-one.

Two divergent series of novel chalcone analogs, one derived from 1-cyclohexylpyrrolidin-2-one and the other derived from 1-benzo[f]chromanone, were designed, synthesized and evaluated for cytotoxicity against two murine cancer cell lines. Two 1-benzo[f]chromanone analogs, 4g and 4j yielded moderate toxicity against both melanoma B16 and lymphoma L1210 cell lines with IC(50) values between the range of 5 and 6 µM. With an IC(50) value of 3.4 µM, compound 4g was also active against human MDA-MB-435 melanoma cells. X-ray structures of the ß-hydroxy ketone product (4a) and the α,ß-unsaturated ketone (4h) were collected, and confirm the syn-configuration between the carbonyl moiety and the ß-vinylic proton in 4h. X-ray structures of two 1-cyclohexylpyrrolidin-2-one derivatives were also obtained, and both showed an E-configuration for the double bond.

5-Benzyl-idene-3-phenyl-2-phenyl-imino-1,3-thia-zolidin-4-one.

The title compound, C(22)H(16)N(2)OS, is a chalcone analog with a thia-zolidinone core that was synthesized as a potential cytotoxic and anti-cancer agent. The structure is commensurately modulated by unit-cell doubling along the direction of the a axis of the cell. The two crystallographically independent mol-ecules are differerentiated by the dihedral angle between the mean planes of the benzyl-idene phenyl group against the thia-zolidin-4-one moiety, which is 5.01 (7)° in one mol-ecule, and 17.41 (6)° in the other. The two mol-ecules are otherwise close to being indistinguishable and are related by crystallographic pseudo-translation. The two mol-ecules are not planar but are slightly bent with the benzyl-idene and phenyl-imino substituents being bent upwards with respect to the center planes of the two mol-ecules. The degree of bending of the two halves of the thia-zolidin-4-one moieties (defined as the planes that inter-sect at the S atom) are 11.08 (7) and 15.88 (7)°. Packing of the mol-ecules is facilitated by C-H⋯π inter-actions and slipped π-π stacking between one of the phenyl rings and a neighboring ethylene π system [distance between the centroid of the ethylene group and the closest phenyl C atom = 3.267 (2) Å, Cg(phenyl)⋯Cg(ethylene) = 3.926 Å].