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Phenothiazines (PTZs) are a group of compounds characterized by the presence of the 10H-dibenzo-[b,e]-1,4-thiazine system. PTZs used in clinics as antipsychotic drugs with other diverse biological activities. The current aim of the study is to investigate and understand the effect of potent PTZs compounds using a group of In-vitro and In-vivo assays. A total of seventeen novel phenothiazine derivatives have been designed, synthesized, and evaluated primarily in-vitro for their ability to inhibit proliferation activity against NCI-60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. Almost all compounds were active and displayed promising cellular activities with GI 50 values in the sub-micromolar range. Four of the most promising derivatives (4b, 4h, 4g and 6e) have been further tested against two selected sensitive cancer cell lines (colon cancer; HCT-116 and breast cancer; MDA-MB231). The apoptosis assay showed that all the selected compounds were able to induce early apoptosis and compound 6e was able to induce additional cellular necrosis. Cell cycle assay showed all selected compounds were able to induce cell cycle arrest at sub-molecular phase of G 0 -G 1 with compound 6e induced cell cycle arrest at G 2 M in HCT-116 cells. Accordingly, the apoptotic effect of the selected compounds was extensively investigated on genetic level and Casp-3, Casp-9 and Bax gene were up-regulated with down-regulation of Bcl-2 gene suggesting the activation of both intrinsic and extrinsic pathways. In-vivo evaluation of the antitumor activity of compound 4b in solid tumor bearing mice showed promising therapeutic effect with manifestation of dose and time dependent toxic effects at higher doses. For better evaluation of the degree of localization of 4b, its 131 I-congener ( 131 I-4b) was injected intravenously in Ehrlich solid tumor bearing mice that showed good localization at tumor site with rapid distribution and clearance from the blood. In-silico study suggested NADPH oxidases (NOXs) as potential molecular target. The compounds introduced in the current study work provided a cutting-edge phenothiazine hybrid scaffold with promising anti-proliferation action that may suggest their anti-cancer activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

There is a continuous need in drug development approach for synthetic anticancer analogues with new therapeutic targets to diminish chemotherapeutic resistance of cancer cells. This study presents new group of synthetic thienopyrimidine analogues (1-9) aims as mGluR-1 inhibitors with anticancer activity. In-vitro antiproliferative assessment was carried out using viability assay against cancer cell lines (MCF-7, A-549 and PC-3) compared to WI-38 normal cell line. Analogues showed variable anticancer activity with IC 50 ranging from 6.60 to 121 µg/mL with compound 7b is the most potent analogue against the three cancer cell lines (MCF-7; 6.57 ± 0.200, A-549; 6.31 ± 0.400, PC-3;7.39 ± 0.500 µg/mL) compared to Doxorubicin, 5-Flurouracil and Riluzole controls. Selected compounds were tested as mGluR-1 inhibitors in MCF-7 cell line and results revealed compound 7b induced significant reduction in extracellular glutamate release (IC 50 ; 4.96 ± 0.700 µM) compared to other analogues and next to Riluzole (IC 50 ; 2.80 ± 0.500 µM) of the same suggested mode of action. Furthermore, both cell cycle and apoptosis assays confirmed the potency of compound 7b for early apoptosis of MCF-7 at G 2 /M phase and apoptotic positive cell shift to (91.4%) compared to untreated control (19.6%) and Raptinal positive control (51.4%). On gene expression level, compound 7b induced over-expression of extrinsic (FasL, TNF-α and Casp-8), intrinsic (Cyt-C, Casp-3, Bax) apoptotic genes with down-regulation of anti-apoptotic Bcl-2 gene with boosted Bax/Bcl-2 ratio to 2.6-fold increase. Molecular docking and dynamic studies confirmed the biological potency through strong binding and stability modes of 7b where it was faster in reaching the equilibrium point and achieving the stability than Riluzole over 20 ns MD. These results suggest compound 7b as a promising mGluR inhibitory scaffold with anticancer activity that deserves further optimization and in-depth In-vivo and clinical investigations., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study synthesizes novel 6-amino-5-cyano-4-aryl-2-mercapto pyrimidines and condensed pyrimidines analogues in order to investigate their potential activity as anticancer agents. The compounds were synthesized via one-pot condensation of p-nitrobenzaldehyde or p-anisaldehyde with malononitrile and thiourea to prepare 6-amino-5-cyano-4-aryl-2-mercaptopyrimidines series (1-9a,b). The pyrimidine analogues were biologically screened In-vitro in HepG2 and MCF-7 compared to normal WI-38. Compound 8a showed higher antiproliferative activity to MCF-7 cells with sensitivity and minimal cytotoxic effect (IC 50 53.3 µM- HepG2, 12.9 µM- MCF-7 and >100 µM- WI-38). Compound 8a was able to induce 40% of total antioxidants and 60% following treatment with 50 µM of H 2 O 2 for 3hrs as external source of oxidative stress in MCF-7. 8a was able to significantly induce early stage apoptosis of 74.37% MCF-7 and cell cycle arrest with cells accumulation in subG 0 -G 1 phase to 69.42% and reduction of cells in G 2 M phase to 3.6% and high apoptotic index. Compound 8a induced over-expression of Fas receptor and Cyto C genes. Molecular docking studies suggested that 8a can bind to both phosphodiesterase 4B and 4D binding pockets and inhibit their action through network of hydrophobic interactions in Q-P pockets with preferential selectivity to PDE4B through invariant Glu443. The chemical profile and the biological results suggest that 8a can be a promising anticancer agent., (Copyright © 2020 Elsevier Inc. All rights reserved.)