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A series of adamantyl carboxamide derivatives containing sulfonate or sulfonamide moiety were designed as multitargeted inhibitors of ectonucleotide pyrophosphatases/phosphodiesterases (NPPs) and carbonic anhydrases (CAs). The target compounds were investigated for their antiproliferative activity against NCI-60 cancer cell lines panel. Three main series composed of 3- and 4-aminophenol, 4-aminoaniline, and 5-hydroxyindole scaffolds were designed based on a lead compound (A). Compounds 1e (benzenesulfonyl) and 1i (4-fluorobenzenesulfonyl) of 4-aminophenol backbone exhibited the most promising antiproliferative activity. Both compounds exhibited a broad-spectrum and potent inhibition against all the nine tested cancer subtypes. Both compounds showed nanomolar IC

The design, synthesis, and biological activities of a new series of pyrazole derivatives are reported. The target compounds 1a-1w were initially investigated against NCI-60 cancer cell lines. Compounds 1f, 1h, 1k, and 1v exerted the highest anti-proliferative activity over the studied panel of cancer cell lines. Compound 1f showed the most potent activity, and it is more potent than sorafenib in 29 cancer cell lines of different types and more potent than SP600125 against almost all the tested cancer cell lines. It also exerted sub-micromolar IC

In the current article, we introduce design of a new series of 4-(imidazol-5-yl)pyridines with improved anticancer activity and selective B-RAF /p38α kinase inhibitory activity. Based on a previous work, a group of structural modifications were applied affording the new potential antiproliferative agents. Towards extensive biological assessment of the target compounds, an in vitro anticancer assay was conducted over NCI 60-cancer cell lines panel representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. Compounds 7c, 7d, 8b, 9b, 9c, 10c, 10d, and 11b exhibited the highest potency among the tested compounds and demonstrated sub-micromolar or one-digit micromolar GI values against the majority of the employed cell lines. Compound 10c emerged as the most potent agent with nano-molar activity over most of the cells and incredible activity against melanoma (MDA-MB-435) cell line (GI 70 nM). It is much more potent than sorafenib, the clinically used anticancer drug, against almost all the NCI-60 cell lines. Further cell-based mechanistic assays showed that compound 10c induced cell cycle arrest and promoted apoptosis in K562, MCF-7 and HT29 cancer cell lines. In addition, compound 10c induced autophagy in the three cancer cell lines. Kinase profiling of 10c showed its inhibitory effects and selectivity towards B-RAF and p38α kinases with IC values of 1.84 and 0.726 µM, respectively. Docking of compound 10c disclosed its high affinity in the kinases pockets. Compound 10c represent a promising anticancer agent, that could be optimized in order to improve its kinase activity aiming at developing potential anticancer agents. The conformational stability of compound 10c in the active site of B-RAF and p38α kinases was studied by applying molecular dynamic simulation of the compound in the two kinases for 600 ns in comparison to the native ligands.

A series of imidazothiazole derivatives possessing potential activity against melanoma cells were investigated for molecular mechanism of action. The target compounds were tested against V600E-B-RAF and RAF1 kinases. Compound 1zb is the most potent against both kinases with IC50 values 0.978 and 8.2 nM, respectively. It showed relative selectivity against V600E mutant B-RAF kinase. Compound 1zb was also tested against four melanoma cell lines and exerted superior potency (IC50 0.18-0.59 µM) compared to the reference standard drug, sorafenib (IC50 1.95-5.45 µM). Compound 1zb demonstrated also prominent selectivity towards melanoma cells than normal skin cells. It was further tested in whole-cell kinase assay and showed in-cell V600E-B-RAF kinase inhibition with IC50 of 0.19 µM. Compound 1zb induces apoptosis not necrosis in the most sensitive melanoma cell line, UACC-62. Furthermore, molecular dynamic and 3D-QSAR studies were done to investigate the binding mode and understand the pharmacophoric features of this series of compounds., Graphical Abstract

In the current article, we introduce design of a new series of 4-(imidazol-5-yl)pyridines with improved anticancer activity and selective B-RAF

The discovery of life-changing medicines continues to be the driving force for the rapid exploration and expansion of chemical space, enabling access to innovative small molecules of medicinal importance. These small molecules remain the backbone for modern drug discovery. In this context, the treatment of ureolytic bacterial infections inspires the identification of potent and effective inhibitors of urease, a promising and highly needed target for H. pylori eradication. The present study explores the evaluation of sulfamate derivatives for the inhibition of urease enzyme. The tested compounds showed remarkable inhibitory effect and high level of potency. Compound 1q emerged as the lead inhibitor with an IC

This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 cancer cell lines of nine cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 μM with broad-spectrum antiproliferative activity. Subsequently, compounds 1j-l were subjected to a dose-response study to measure their GI

This article reports on novel imidazothiazole derivatives as first-in-class potent and selective ErbB4 (HER4) inhibitors. There are no other reported selective inhibitors of this kinase in the literature, that's why they are considered as first-in-class. In addition, none of the reported non-selective ErbB4 inhibitors possesses imidazothiazole nucleus in its structure. Therefore, there is novelty in this work in both kinase selectivity and chemical structure. Compounds Ik and IIa are the most potent ErbB4 kinase inhibitor (IC50 = 15.24 and 17.70 nM, respectively). Compound Ik showed promising antiproliferative activity. It is selective towards cancer cell lines than normal cells. Its ability to penetrate T-47D cell membrane and inhibit ErbB4 kinase inside the cells has been confirmed. Moreover, both compound Ik and IIa have additional merits such as weak potency against hERG ion channels and against CYP 3A4 and 2D6. Molecular docking and dynamic simulation studies were carried out to explain binding interactions.

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives possessing a terminal sulfonamide moiety were synthesized. Pan-RAF inhibitory effect of the new series was investigated, and structure-activity relationship is discussed. Antiproliferative activity of the target compounds was tested against the NCI-60 cell line panel. The most active compounds were further tested to obtain their IC50 values against cancer cells. Compound 27c with terminal open chain sulfonamide and 38a with a cyclic sulfamide moiety showed the highest activity in enzymatic and cellular assay, and both compounds were able to inhibit phosphorylation of MEK and ERK. Compound 38a was selected for testing its in vivo activity against melanoma. Cellular and animal activities are reported.

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1

The synergistic effect of dual inhibition of serine/threonine protein kinases that are involved in the same signalling pathway of the diseases can exert superior biological benefits for treatment of these diseases. In the present work, a new series of (imidazol-5-yl)pyrimidine was designed and synthesized as dual inhibitors of BRAFV600E and p38α kinases which are considered as key regulators in mitogen-activated protein kinase (MAPK) signalling pathway. The target compounds were evaluated for dual kinase inhibitory activity. The tested compounds exhibited nanomolar scale IC50 values against BRAFV600E and low to sub-micromolar IC50 range against p38α. Compound 20h was identified as the most potent dual BRAFV600E/p38α inhibitor with IC50 values of 2.49 and 85 nM, respectively. Further deep investigation revealed that compound 20h possesses inhibitory activity of TNF-α production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 value of 96.3 nM. Additionally, the target compounds efficiently frustrated the proliferation of LOX-IMVI melanoma cell line. Compound 20h showed a satisfactory antiproliferative activity with IC50 value of 13 μM, while, compound 18f exhibited the highest cytotoxicity potency with IC50 value of 0.9 μM. Compound 18f is 11.11-fold more selective toward LOX-IMVI melanoma cells than IOSE-80PC normal cells. The newly reported compounds represent therapeutically promising candidates for further development of BRAFV600E/p38α inhibitors in an attempt to overcome the acquired resistance of BRAF mutant melanoma.

Introduction: Steroid sulfatase (STS) enzyme is responsible for transforming the inactive sulfate metabolites of steroid sex hormones into the active free steroids. Both the deficiency and the over-expression of STS are associated with the pathophysiology of certain diseases. This article provides the readership with a comprehensive review about STS enzyme and its recently reported inhibitors.Areas covered: In the present article, we reviewed the structure, location, and substrates of STS enzyme, physiological functions of STS, and disease states related to over-expression or deficiency of STS enzyme. STS inhibitors reported during the last five years (2016-present) have been reviewed as well.Expert opinion: Irosustat is the most successful STS inhibitor drug candidate so far. It is currently under investigation in clinical trials for treatment of estrogen-dependent breast cancer. Non-steroidal sulfamate is the most favorable scaffold for STS inhibitor design. They can be beneficial for the treatment of hormone-dependent cancers and neurodegenerative disorders without significant estrogenic side effects. Moreover, dual-acting molecules (inhibitors of STS + another synergistic mechanism) can be therapeutically efficient.

P38α (which is also named MAPK14) plays a pivotal role in initiating different disease states such as inflammatory disorders, neurodegenerative diseases, cardiovascular cases, and cancer. Inhibitors of p38α can be utilized for treatment of these diseases. In this article, we reviewed the structural and biological characteristics of p38α, its relationship to the fore-mentioned disease states, as well as the recently reported inhibitors and classified them according to their chemical structures. We focused on the articles published in the literature during the last decade (2011-2020).

The synergistic effect of dual inhibition of serine/threonine protein kinases that are involved in the same signalling pathway of the diseases can exert superior biological benefits for treatment of these diseases. In the present work, a new series of (imidazol-5-yl)pyrimidine was designed and synthesized as dual inhibitors of BRAF

Alkaline phosphatases are found in different living species and play crucial roles in various significant functions, such as hydrolyzing a variable spectrum of phosphate-containing physiological compounds, contributing to DNA synthesis, bone calcification, and attenuation of inflammation. They are homodimeric enzymes; each subunit contains one magnesium ion and two zinc ions crucial for the catalytic activity of the enzyme. Alkaline phosphatases exist in four distinct isoenzymes (placental, intestinal, germ cell, and tissue nonspecific alkaline phosphatases), which are expressed by four different genes; each one of them has distinguished functions. Any disturbance in the gene expression of alkaline phosphatase eventually induces serious disease conditions. Thus, the need to explore new lead inhibitors has increased recently. In this literature review, we aim to investigate the role of alkaline phosphatase in different diseases and physiological conditions and to study the structure-activity relationships of recently reported inhibitors. We focused on the lead compounds reported in the last 5 years (between 2015 and 2019).

Tissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellular matrix calcification during bone formation and growth. The elevated level of TNAP has been linked to vascular calcification and end-stage renal diseases. Consequently, there is a need to search for highly potent and selective inhibitors of alkaline phosphatases (APs) for treatment of disorders associated with the over-expression of APs. Herein, a series of tricyclic coumarin sulphonate 1a-za with known antiproliferative activity, was evaluated for AP inhibition against human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). The methylbenzenesulphonate derivative 1f (IC50 = 0.38 ± 0.01 μM) was found to be the most active h-TNAP inhibitor. Another 4-fluorobenzenesulphonate derivative 1i (IC50 = 0.45 ± 0.02 μM) was found as the strongest inhibitor of h-IAP. Some of the derivatives were also identified as highly selective inhibitors of APs. Detailed structure-activity relationship (SAR) was investigated to identify the functional groups responsible for the effective inhibition of AP isozymes. The study was also supported by the docking studies to rationalise the most possible binding site interactions of the identified inhibitors with the targeted enzymes.

Colony stimulation factor-1 receptor (CSF-1R), which is also known as FMS kinase, plays an important role in initiating inflammatory, cancer, and bone disorders when it is overstimulated by its ligand, CSF-1. Innate immunity, as well as macrophage differentiation and survival, are regulated by the stimulation of the CSF-1R. Another ligand, interlukin-34 (IL-34), was recently reported to activate the CSF-1R receptor in a different manner. The relationship between CSF-1R and microglia has been reviewed. Both CSF-1 antibodies and small molecule CSF-1R kinase inhibitors have now been tested in animal models and in humans. In this Perspective, we discuss the role of CSF-1 and IL-34 in producing cancer, bone disorders, and inflammation. We also review the newly discovered and improved small molecule kinase inhibitors and monoclonal antibodies that have shown potent activity toward CSF-1R, reported from 2012 until 2017.

The inhibition of nitric oxide and prostaglandin E2 productions is a very interesting research topic in the field of anti-inflammatory drug development. In the current study, a new series of 1,3,4-triarylpyrazole derivatives was synthesized and evaluated for their capabilities to inhibit nitric oxide and prostaglandin E2 productions in lipopolysaccharide-induced RAW 264.7 macrophages. Among all the target analogs, the diarylurea hydroxyl compounds 1f and 1h possessing phenyl and 3-(trifluoromethyl)phenyl terminal moiety, respectively, showed the highest inhibitory effect on the production of prostaglandin E2. Both compounds exerted equal activity to the reference compound NS-398 at 3 µM concentration. This effect was due to inhibition cyclooxygenase-2 enzyme activity not inhibition of cyclooxygenase-2 protein expression. The IC50 value of compound 1f against lipopolysaccharide-induced prostaglandin E2 production in the macrophages was 1.12 μM. In addition, compound 1j with urea linker, hydroxyl group, and 3,5-bis(trifluoromethyl)phenyl terminal ring was the strongest nitric oxide inhibitor. Western blot study showed that it exerted that effect through inhibition of inducible nitric oxide synthase protein expression.

Carbapenems are among the most commonly used and the most efficient antibiotics since they are relatively resistant to hydrolysis by most β-lactamases, they target penicillin-binding proteins, and generally have broad-spectrum antibacterial effect. In this review, we described the initial discovery and development of carbapenems, chemical characteristics, in vitro/in vivo activities, resistance studies, and clinical investigations for traditional carbapenem antibiotics in the market; imipenem-cilastatin, meropenem, ertapenem, doripenem, biapenem, panipenem/betamipron in addition to newer carbapenems such as razupenem, tebipenem, tomopenem, and sanfetrinem. We focused on the literature published from 2010 to 2016.

Several pyrrolopyridines or azaindoles have been reported in the literature as biologically-active molecules. Most of them are anticancer agents, and few possess other therapeutic effects. Areas covered: The most recent biologically-active pyrrolopyridine derivatives have been reviewed from the patents and research articles published from 2010 to the mid of 2016. Their structural and biological features have been explained. In general, the pyrrolopyridine scaffold mimics the purine ring of the ATP molecule. So the well-designed pyrrolopyridine analogues can successfully act as kinase inhibitors for treatment of cancer and/or other diseases. The most successful pyrrolopyridine derivative that is currently used in the market is vemurafenib, which is used for treatment of melanoma. Its chemical and biological features have been reviewed and explained. Expert opinion: The heterocyclic pyrrolopyridine nucleus mimics the purine ring of ATP. So they can work as inhibitors of the kinase at hinge region. Due to the structural similarity with ATP, these pyrrolopyridine derivatives are estimated to be non-selective kinase inhibitors. The selectivity is conferred mainly from the different substituents attached to the azaindole nucleus. More details are presented in the 'Expert Opinion' section at the end of this article. This section covers the chemistry and the biological properties of therapeutically-efficient pyrrolopyridine-possessing compounds.

Background: Pyrazole derivatives have been reported as both anticancer and antiinflammatory agents. Objective: This study was conducted to develop new pyrazole derivatives as potential anticancer and/or antiinflammatory agents. Their molecular mechanisms of action have been investigated. Method: a series of new triarylpyrazole derivatives were synthesized. Their in vitro anticancer activity was tested against NCI-58 cancer cell line panel of nine cancer types. The most active compound 1a was tested against sixteen kinases, many of them are known to be over-expressed in leukemia and breast cancer. The most sensitive kinases were V600E-B-RAF, C-RAF, FLT3, and P38α/MAPK14. Compound 1a was further tested for caspase-3/7 activity and LDH release assay as measures of its apoptotic and necrotic activities against RPMI-8226. Moreover, the ability of compounds 1a, 1b, and 1g to inhibit nitric oxide and prostaglandin E2production in LPS-induced RAW 264.7 macrophages was also examined. Results: Compounds 1a, 1c, and 1g showed the highest activities against the cancer cell line panel, with more inhibitory effects against leukemia and breast cancer subpanels. The highest activity was exerted by compound 1a. Its IC50 values against RPMI-8226, K-562 leukemia cell lines, and MDA-MB-468 breast cancer cell line were 1.71 μM, 3.42 μM, and 6.70 μM, respectively. The IC50 of compound 1a against P38α/MAPK14 kinase was 0.515 μM. The caspase activity was increased by 72% and 170% at 1.23 μM and 3.70 μM concentrations of compound 1a, respectively. Furthermore, compound 1b inhibited 80.26% and 95.31% of NO and PGE2 productions, respectively, at 50 μM concentration in the LPS-induced RAW 264.7 macrophages. Conclusion: Compound 1a could kill the cells through induction of apoptosis rather than necrosis. Compound 1a was more selective against cancer cells than non-cancerous cells. In addition, the hydroxyl analogue 1b was the most active as antiinflammatory agent.

Several diarylamide compounds have been highlighted as potential anticancer agents. Among them, imatinib, dasatinib, and nilotinib have been marketed for treatment of chronic myeloid leukemia (CML). CML is a cancer type that originates in specific cells in bone marrow and is considered as life-threating disease. Imatinib is the first generation of tyrosine kinase inhibitor (TKI) to be approved for treatment of CML. Second generation drugs, dasatinib and nilotinib, were introduced for patients that are resistant or intolerant to imatinib therapy. Second generation drugs induce faster responses with fewer side effects when compared to imatinib. In this literature review, we reviewed recent advances of diarylamide anticancer agents, including first and second generation drugs treating CML and their other uses, in addition to other compounds that are still in preclinical phases. This review focuses on the reports published in the literature from 2010 to 2019.

In this article, a series of 22 triarylpyrazole derivatives were evaluated for in vitro antiinflammatory activity as inhibitors of nitric oxide (NO) and prostaglandin E

In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a–t, having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH2, NHMe, or NMe2) was designed and synthesized. Most of the derivatives exhibited higher potency than acetazolamide as inhibitors of the purified hCAII, IX and XII isoforms. The most potent inhibitors for hCAII, hCAIX and hCAXII were 1g, 1b and 1d with an IC50 ± SEM values of 0.14 ± 0.03, 0.13 ± 0.03 and 0.17 ± 0.06 µM, respectively. In addition, compounds 1d and 1n exerted preferential inhibitory effect against hCAXII isozyme with good potencies. Some selected compounds were docked within the active pocket of these isozymes and binding of the molecules revealed that sulfonate and sulfamate rings were located towards the active cavity and compounds coordinated to zinc ions.

In the present article, we reviewed the sulfamate-containing compounds reported as bioactive molecules. The possible molecular targets of sulfamate derivatives include steroid sulfatase enzyme, carbonic anhydrases, acyl transferase, and others. Sulfamate derivatives can help treat hormone-dependent tumors including breast, prostate, and endometrial cancers, Binge eating disorder, migraine, glaucoma, weight loss, and epilepsy. Sulfamate derivatives can act also as calcium sensing receptor agonists and can aid in osteoporosis. Furthermore, acyl sulfamate derivatives can act as antibacterial agents against Gram-positive bacteria. A recent study revealed a new side effect of topiramate, a sulfamate-containing compound, which is sialolithiasis. The structural and biological characteristics of the reviewed compounds are presented in detail.