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A series of thieno[2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC50=185 nM), potent EGFR inhibition (IC50=1.14 µM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC50=19 nM) and (IC50=5.58 µM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC50= 68 nM and VEGFR2 IC50= 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.

A facile and efficient One-pot procedure was achieved for the synthesis of thiazol-2(3H)-imine derivatives through the bromination of some α-active methylene ketones followed by treatment with potassium thiocyanate and condensation with various primary amines in ethanol as one-pot four-step process. The α-active methylene ketones were symmetrical and asymmetrical ketones. The primary amines used were mostly aromatic amines and also benzylamine was used. This proposed method does not require the use of techniques such as extraction and chromatography. Surprisingly, the product from the reaction of 3-thiocyanacetylacetone and benzylamine was elucidated to be N-(3-benzyl-4-hydroxy-4-methylthiazolidin-2-ylidene)acetamide (2) and not the expected compound 1-(3-benzyl-2-imino-4-methyl-2,3-dihydrothiazol-5-yl)ethan-1-one (1),which was proved based on the existence of the methylene and hydroxyl group in the compound.The mechanism of the novel compound 2 was confirmed by subsequent chemical reactions, spectroscopic data and X-ray crystallography.The molecular structure of all newly synthesized thiazol-2(3H)-imine derivatives were elucidated on the basis of spectroscopic dataand elemental analysis.

Breast cancer (BC) and endocrine resistance to chemotherapy are challenging problems where angiogenesis plays fundamental roles. Thus, targeting of VEGFR-2 signalling pathway has been an attractive approach. In this study, we synthesised a new sorafenib analogue, thieno[2,3-d]pyrimidine based urea derivative, KM6. It showed 65% inhibition of VEGF2 tyrosine kinase activity and demonstrated a potential antitumor activity in TAM-resistant, LCC2, and its parental MCF7 BC cells. KM6 retained the sensitivity of LCC2 through upregulation of key enzymes of apoptosis and proteins of cell death including caspases 3, 8, 9, P53, BAX/BCL-2 ratio and LDH in media. It downregulated mRNA expression of Ki-67, survivin, Akt, and reduced levels of ROS and glucose uptake. Moreover, KM6 reduced the levels of inflammation markers PGE2, COX2, IL-1β and IL6 and metastasis markers MMP-2 and MMP-9. In conclusion, KM6 is a promising compound for ER + and TAM-resistant BC with many potential antitumor and polypharmacological mechanisms., Graphical Abstract

Corticotrophin releasing factor receptor-1 (CRFR1) is a potential target for treatment of depression and anxiety through modifying stress response. A series of new thiazolo[4,5-d]pyrimidine derivatives were designed, prepared and biologically evaluated as potential CRFR1 antagonists. Four compounds produced more than fifty percent inhibition in the [125I]-Tyr0-sauvagine specific binding assay. Assessment of binding affinities revealed that compound (3-(2,4-dimethoxyphenyl)-7-(dipropylamino)-5-methylthiazolo[4,5-d]pyrimidin-2(3H)-one) 8c was the best candidate with highest binding affinity (Ki = 32.1 nM). Further evaluation showed the ability of compound 8c to inhibit CRF induced cAMP accumulation in a dose response manner. Docking and molecular dynamics simulations were used to investigate potential binding modes of synthesized compounds as well as the stability of 8c-CRFR1 complex. These studies suggest similar allosteric binding of 8c compared to that of the co-crystalized ligand CP-376395 in 4K5Y pdb file.

Graphical abstract, This work was a structured virtual screening for marine bioactive compounds with reported antiviral activities which were subjected to structure-based studies against SARS-CoV-2 co-crystallized proteins. The molecular docking of marine bioactive compounds against the main protease (Mpro, PDB ID: 6lu7 and 6y2f), the spike glycoprotein (PDB ID: 6vsb), and the RNA polymerase (PDB ID: 6m71) of SARS-CoV-2 was performed. Ligand-based approach with the inclusion of rapid overlay chemical structures (ROCS) was also addressed in order to examine the probability of these marine compounds sharing relevance and druggability with the reported drugs. Among the examined marine library, the highest scores in different virtual screening aspects were displayed by compounds with flavonoids core, acyl indole, and pyrrole carboxamide alkaloids. Moreover, complete overlay with the co-crystallized ligands of Mpro was revealed by sceptrin and debromo-sceptrin. Thalassoilin (A-B) which found in the Red Sea exhibited the highest binding and similarity outcomes among all target proteins. These data highlight the importance of marine natural metabolites in regard of further studies for discovering new drugs to combat the COVID-19 pandemic.

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.

Apoptosis is a chief regulator of cellular homeostasis. Impairment of apoptotic machinery is a main characteristic of several diseases such as cancer, where the evasion of apoptosis is a cardinal hallmark of cancer. Apoptosis is regulated by contribution of pro- and anti- apoptotic proteins, where caspases are the main executioners of the apoptotic machinery. IAP (inhibitors of apoptosis proteins) is a family of endogenous inhibitors of apoptosis, which perform their function through interference with the function of caspases. Smac (second mitochondria-derived activator of caspases) is endogenous inhibitor of IAPs, thus it is one of the major proapoptotic endogenous proteins. Thus, the development of Smac mimetics has evolved as an approach for anticancer therapy. Several Smac mimetic agents have been introduced to clinical trial such as birinapanet 12. Herein, the history of development of Smac mimetics along with the recent development in this field is briefly discussed.

Context Extensive research conducted within past years revealed that curcumin is a highly pleiotropic molecule that interacts with a diverse range of molecular targets and hence it possess anti-proliferative activities against tumor cells.The great similarities between curcumin analogs and chalcones inspired their testing against tubulin enzyme activity as recent research revealed that chalcones possess cytotoxic activity associated with tubulin inhibition and interference with microtubule formation, which is essential in mitosis and cell replication. Objective Novel Curcumin analogs were designed, synthesized and tested for their antitumor activities. Also in silico and in vitro studies has been performed to predict the binding affinity of the target compounds and to test their ability to inhibit tubulin assembly and act as microtubule destabilizing agents. Methods Six novel curcumin analogs were designed & synthesized with 3,5-dibenzylidenepiperidin-4-one core moiety. Results Compounds showed interaction energy comparable to or within the range of podophyllotoxin itself when docked into the colchicine binding site of tubulin using the podophyllotoxin-tubulin complex (PDB 1SA1 ). Conclusion Compounds showed moderate anticancer activity and moderate ability to destabilize microtubules and thus inhibiting tubulin polymerization, as a result; these compounds could be used for further future development to obtain more potent analogs.

CB2-based therapeutics show strong potential in the treatment of diverse diseases such as inflammation, multiple sclerosis, pain, immune-related disorders, osteoporosis and cancer, without eliciting the typical neurobehavioral side effects of CB1 ligands. For this reason, research activities are currently directed towards the development of CB2 selective ligands. Herein, the synthesis of novel heterocyclic-based CB2 selective compounds is reported. A set of 2,5-dialkyl-1-phenyl-1H-pyrrole-3-carboxamides, 5subtituted-2-(acylamino)/(2-sulphonylamino)-thiophene-3-carboxylates and 2-(acylamino)/(2sulphonylamino)-tetrahydrobenzo[b]thiophene-3-carboxylates were synthesized. Biological results revealed compounds with remarkably high CB2 binding affinity and CB2/CB1 subtype selectivity. Compound 19a and 19b from the pyrrole series exhibited the highest CB2 receptor affinity (K-i; = 7.59 and 6.15 nM, respectively), as well as the highest CB2/CB1 subtype selectivity (similar to 70 and similar to 200-fold, respectively). In addition, compound 6b from the tetrahydrobenzo[b]thiophene series presented the most potent and selective CB2 ligand in this series (K-i; = 2.15 nM and CB2 subtype selectivity of almost 500-fold over CB1). Compound 6b showed a full agonism, while compounds 19a and 19b acted as inverse agonists when tested in an adenylate cyclase assay. The present findings thus pave the way to the design and optimization of heterocyclic-based scaffolds with lipophilic carboxamide and/or retroamide substituent that can be exploited as potential CB2 receptor activity modulators. (C) 2016 Elsevier Masson SAS. All rights reserved.

Sulphonamides embrace a sublime class of drugs with various biological activities. Since the discovery of E7010 in 1992, several sulphonamides as anti-cancer drug candidates have been identified. Herein, a new series of 5-chloro- 2-methoxy-N-(4-sulphamoylphenyl) benzamide derivatives was synthesised, and their anti-proliferative activity was evaluated against human ovarian cancer (A2780) and colon cancer (HCT-116) cell lines. As one of the most potent antiproliferative agents, compound 4j was further tested against a panel of cancer cell lines revealing that human pancreatic carcinoma (MIA PaCa-2) displayed the highest sensitivity. Cellular mechanistic studies on MIA PaCa-2 cells showed that 4j arrested the G2/M cell cycle and induced apoptosis. Refereed/Peer-reviewed