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Amit K Keshari,1 Ashok K Singh,1 Umesh Kumar,2 Vinit Raj,1 Amit Rai,1 Pranesh Kumar,1 Dinesh Kumar,2 Biswanath Maity,2 Sneha Nath,3 Anand Prakash,3 Sudipta Saha11Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, 2Centre of Biomedical Research, SGPGIMS Campus, 3Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, IndiaAbstract: 5H-benzo[h]thiazolo[2,3-b]quinazoline scaffold is known to have an antitumor effect on certain types of malignancies; however, its effect on hepatocellular carcinoma (HCC) remains unclear. Previously, we reported p-toluenesulfonic acid-promoted syntheses, molecular modeling and in vitro antitumor activity of 5H-benzo[h]thiazolo[2,3-b]quinazoline against human hepatoma (Hep-G2) cells where compounds 4A and 6A were found to be potent inhibitors among the series. In continuation to our previous effort to develop novel therapeutic strategies for HCC treatment, here we investigated the in vivo antitumor activity and the mechanism underlying the effects of 4A and 6A in N-nitrosodiethylamine (NDEA)-induced HCC using male Wistar rats. NDEA was administered weekly intraperitoneally at a dose of 100 mg/kg for 6 weeks. Various physiological and morphological changes, oxidative parameters, liver marker enzymes and cytokines were assessed to evaluate the antitumor effect of 4A and 6A. In addition, proton nuclear magnetic resonance-based serum metabolomics were performed to analyze the effects of 4A and 6A against HCC-induced metabolic alterations. Significant tumor incidences with an imbalance in carcinogen metabolizing enzymes and cellular redox status were observed in carcinogenic rats. Tumor inhibitory effects of 4A and 6A were noted by histopathology and biochemical profiles in NDEA-induced hepatic cancer. Compounds 4A and 6A had a potential role in normalizing the elevated levels of inflammatory mediators such as interleukin-1β (IL-1β), IL-2, IL-6 and IL-10. At molecular level, the real-time quantitative reverse-transcribed polymerase chain reaction analysis revealed that 4A and 6A attenuated the IL-6 gene overexpression in hepatic cancer. Further, orthogonal partial least squares discriminant analysis scores plot demonstrated a significant separation of 4A and 6A-treated groups from carcinogen control group. Both the compounds have potential to restore the imbalanced metabolites due to HCC, signifying promising hepatoprotective activities. All these findings suggested that 4A and 6A could be potential drug candidates to treat HCC.Keywords: 5H-benzo[h]thiazolo[2,3-b]quinazoline, N-nitrosodiethylamine, NDEA, hepatocellular carcinoma, HCC, interleukins, 1H-NMR based metabolomics

Amit K Keshari,1 Ashok K Singh,1 Vinit Raj,1 Amit Rai,1 Prakruti Trivedi,2 Balaram Ghosh,2 Umesh Kumar,3 Atul Rawat,3 Dinesh Kumar,3 Sudipta Saha1 1Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 2Department of Pharmacy, Birla Institute of Technology & Science Pilani, Hyderabad Campus, Hyderabad, Telangana State, 3Centre of Biomedical Research (CBMR), Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, India Abstract: In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a p-toluenesulfonic acid (p-TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogs bearing a bridgehead nitrogen atom. This domino protocol constructed one new ring by the concomitant formation of multiple bonds (C–C, C–N, and C=N) involving multiple steps without the use of any metal catalysts in one-pot, with all reactants efficiently exploited. All the newly synthesized compounds were authenticated by means of Fourier transform infrared spectroscopy, liquid chromatography–mass spectrometry, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy, together with elemental analysis, and their antitumor activity was evaluated in vitro on a Hep-G2 human cancer cell line by sulforhodamine B assay. Computational molecular modeling studies were carried out on cancer-related targets, including interleukin-2, interleukin-6, Caspase-3, and Caspase-8. Two compounds (4A and 6A) showed growth inhibitory activity comparable to the positive control Adriamycin, with growth inhibition of 50%

12H-Benzo[1,3]oxazolo[2,3-b]quinazolin-12-imine (5a), 9-chloro-12Hbenzo[1,3]oxazolo[2,3-b]quinazolin-12-imine (5b), 2,3-dihydro-5H-[1,3]oxazolo[2,3-b]quinazolin-5-imine (5c), 2,3-dihydro-3,3-dimethyl-5H-[1,3]oxazolo[2,3-b]quinazolin-5-imine (5d) and 3,4--dihydro-2H,6H-[1,3]oxazino[2,3-b]quinazolin-6-imine (5e) were synthesized in a one-pot reaction of N-(2-cyanophenyl)chloromethanimidoyl chloride (1) with 2-aminophenols, 2-aminoethanol, and 3-aminopropanol in the presence of a base. The course of the reaction was controlled by the temperature and the amount of base used. N-(2-Cyanophenyl)-(2-hydroxyanilino)methanimidoyl chloride (3a), 2-chloro-3-(2-hydroxyphenyl)-3,4-dihydroquinazolin-4-imine (4a) and 6-imino-2H, 3H, 4H, 6H, 11H-1,3-oxazino[2,3-b]-5-quinazolinium chloride (6) were identified as intermediates of the one-pot process.

Background: There are only limited publications devoted to the synthesis of especially thiazolo[3,2-a]quinazoline which involved reaction of 2-mercaptopropargyl quinazolin-4-one with various aryl iodides catalyzed by Pd-Cu or by condensation of 2-mercapto-4-oxoquinazoline with chloroacetic acid, inspite of this procedure was also reported in the literature to afford the thiazolo [2,3-b] quinazoline. So the multistep synthesis of the thiazolo[3,2-a]- quinazoline suffered from some flaws and in this study we have synthesized a novel class of thiazoloquinazolines by a simple and convenient method involving catalysis by 1,4-diazabicyclo[2.2.2]octane (DABCO). Results: A new and convenient one-pot synthesis of a novel class of 2-arylidene-2H-thiazolo[3,2-a]quinazoline-1, 5-diones 9a-i was established through the reaction between methyl-2-(2-thio-cyanatoacetamido)benzoate (4) and a variety of arylidene malononitriles 8a-i in the presence of DABCO as a mild and efficient catalytic system via a Michael type addition reaction and a mechanism for formation of the products observed is proposed. Moreover 4 was converted to ethyl-2-[(4-oxo-3,4-dihydroquinazolin-2-yl)thio]acetate (10) upon reflux in ethanol containing DABCO as catalyst. The latter was reacted with aromatic aldehydes and dimethylformamide dimethylacetal (DMF-DMA) to afford a mixture of two regioselectively products with identical percentage yield, these two products were identified as thiazolo[3,2-a]quinazoline 9,13 and thiazolo[2,3-b]quinazoline 11,12 derivatives respectively. The structure of the compounds prepared in this study was elucidated by different spectroscopic tools of analyses also the X-ray single crystal technique was employed in this study for structure elucidation, Z/E potential isomerism configuration determination and to determine the regioselectivity of the reactions. Conclusion: A simple and efficient one-pot synthesis of a novel class of 2-arylidene-2H-thiazolo[3,2-a]quinazoline-1, 5-diones 9a-i was established through DABCO catalyzed Michael type addition reaction. In addition many fused quinazoline and quinazoline derivatives were synthesized which appeared as valuable precursors in synthetic and medicinal chemistry. [ABSTRACT FROM AUTHOR]