Combining lavendustin C and 5-arylidenethiazolin-4-one-based pharmacophores toward multitarget anticancer hybrids.

Lavendustin C, a natural-product derived anticancer lead compound, was modified at its carboxylic group by esterification or amidation (compounds 6-10) and at its amino group by introducing 5-arylidenethiazolin-4-ones (14a-c to 17a-c, 18a and 18b). Two strategies were used to combine these moieties and to optimize the yield. These new compounds were evaluated for their antiproliferative activities against a panel of nine cancer cell lines.

Neu5Gc-mediated high-affinity interaction is dispensable for CD22 cis-ligands to regulate B cell signaling.

CD22 (also known as Siglec-2) is an inhibitory receptor expressed in B cells. CD22 specifically recognizes α2,6 sialic acid and interacts with α2,6 sialylated membrane proteins expressed on the same cell (cis-ligands) and those derived from outside of the cell (trans-ligands). Previously, CD22 cis-ligands were shown to regulate the activity of CD22, thereby regulating both BCR ligation-induced signaling and low-level "tonic" signaling in the absence of BCR ligation that regulates the survival and differentiation of B cells.

Design, synthesis, biological evaluation and docking study of some new aryl and heteroaryl thiomannosides as FimH antagonists.

FimH is a mannose-recognizing lectin that is expressed by Escherichia coli guiding its ability to adhere and infect cells. It is involved in pathogenesis of urinary tract infections and Chron's disease. Several X-ray structure-guided ligand design studies were extensively utilized in the discovery and optimization of small molecule aryl mannoside FimH antagonists.

Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives.

The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids ( and ) from 5-aminosalicylic acid and 4-thiazolinone derivatives.

New nitazoxanide derivatives: design, synthesis, biological evaluation, and molecular docking studies as antibacterial and antimycobacterial agents.

A new series inspired by combining fragments from nitazoxanide (NTZ) and 4-aminosalicylic acid (4-ASA) was synthesized and screened for antibacterial and antimycobacterial activities. The majority showed higher antibacterial potency than NTZ against all the screened strains, notably, 5f, 5j, 5n and 5o with MICs of 0.87-9.

The design, synthesis, biological evaluation, and molecular docking of new 5-aminosalicylamide-4-thiazolinone hybrids as anticancer agents.

New 5-aminosalicylamide-4-thiazolinone hybrids (27) were efficiently synthesized, characterized, and evaluated to explore their structure-activity relationship as anticancer agents. The antiproliferative activities of the new hybrids were evaluated against eight cancer cell lines using the sulforhodamine B assay. The most potent compound (24b) possessed high selectivity on the tested cell lines in the low micromolar range, with much lower effects on normal fibroblast cells (IC > 50 µM).

Synthesis, biological evaluation and molecular docking study of some new 4-aminosalicylic acid derivatives as anti-inflammatory and antimycobacterial agents.

In this study, new derivatives of the antitubercular and anti-inflammatory drug, 4-aminosaliclic acids (4-ASA) were synthesized, characterized, and evaluated for these activities. In vivo and in viro evaluation of anti-inflammatory activity revealed that compounds 10, 19 and 20 are the most active with potent cyclooxygenase-2 (COX-2) and 5-lipooxgenase (5-LOX) inhibition and without causing gasric lesions. The minimum inhibitory concentrations (MIC) of the newly synthesized compound were, also, measured against Mycobacterium tuberculosis H37RV.

The inhibitory coreceptor CD22 restores B cell signaling by developmentally regulating immunodeficient B cells.

The protein tyrosine phosphatase CD45 plays a crucial role in B cell antigen receptor (BCR) signaling by activating Src family kinases. mice show altered B cell development and a phenotype likely due to reduced steady-state signaling; however, B cells show relatively normal BCR ligation-induced signaling. In our investigation of how BCR signaling was restored in cells, we found that the coreceptor CD22 switched from an inhibitory to a stimulatory function in these cells.

Crystal structure and Hirshfeld surface analysis of 5-acetyl-3-amino-6-methyl--phenyl-4-[()-2-phenyl-ethen-yl]thieno[2,3-]pyridine-2-carbox-amide.

The asymmetric unit of the title compound, CHNOS, comprises four mol-ecules. Their conformations differ primarily in the orientations of the styryl and the -phenyl-carboxamido groups. In the crystal, inter-molecular N-H⋯N, C-H⋯O and C-H⋯S hydrogen-bonding contacts as well a C-H⋯π(ring) inter-actions lead to the formation of a layer structure parallel to (010).

The Protein Tyrosine Phosphatase SHP-1 (PTPN6) but Not CD45 (PTPRC) Is Essential for the Ligand-Mediated Regulation of CD22 in BCR-Ligated B Cells.

CD22 is an inhibitory B cell coreceptor that regulates B cell development and activation by downregulating BCR signaling through activation of SH2-containing protein tyrosine phosphatase-1 (SHP-1). CD22 recognizes α2,6 sialic acid as a specific ligand and interacts with α2,6 sialic acid-containing membrane molecules, such as CD45, IgM, and CD22, expressed on the same cell. Functional regulation of CD22 by these endogenous ligands enhances BCR ligation-induced signaling and is essential for normal B cell responses to Ags.

Design, synthesis and molecular docking study of α-triazolylsialosides as non-hydrolyzable and potent CD22 ligands.

Ligand 1 was the first reported example of monomeric high-affinity synthetic CD22 ligand that regulated B cell activation in vitro, augmented antibody production and regulated immune responses in mice. Replacing O-glycoside linkage of 1 by nitrogen of triazole by click reaction afforded compounds which are as potent as the parent compound. The synthesis of the new compounds is straightforward with fewer synthetic steps and higher yield.

Design and synthesis of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as antiproliferative EGFR and BRAF dual inhibitors.

Recent studies have shown additive and synergistic effects associated with the combination of kinase inhibitors. BRAF and EGFR are attractive targets for many diseases treatments and have been studied extensively. In keeping with our interest in developing anticancer targeting EGFR and BRAF, a novel series of 2,3-dihydropyrazino[1,2-a]indole-1,4-dione has been rationally designed, synthesized and evaluated for their antiproliferative activity against a panel of four human cancer cell lines.

Induction of DNA damage, apoptosis and cell cycle perturbation mediate cytotoxic activity of new 5-aminosalicylate-4-thiazolinone hybrid derivatives.

Modulation of several targets in cancer cells enhances the effect of anti-cancer drugs. This can be achieved by using combinations of anti-cancer drugs or by designing new drugs with novel pharmacophore structures that target different molecules within cancer cells. We developed a panel of such compounds by accommodating two chemical entities (5-Aminoslicylic acid and thiazolin-4-one) known to have anti-cancer activities into a single framework structure.

Further insight into the dual COX-2 and 15-LOX anti-inflammatory activity of 1,3,4-thiadiazole-thiazolidinone hybrids: The contribution of the substituents at 5th positions is size dependent.

Herin we report the design, synthesis, full characterization and biological investigation of new 15-LOX/COX dual inhibitors based on 1,3-thiazolidin-4-one (15-lipoxygenase pharmacophore) and 1,3,4-thiadiazole (COX pharmacophore) scaffolds. This series of molecular modifications is an extension of a previously reported series to further explore the structural activity relationship. Compounds 3a, 4e, 4n, 4q, 7 and 8 capable of inhibiting 15-LOX at (2.

Click chemistry synthesis, biological evaluation and docking study of some novel 2'-hydroxychalcone-triazole hybrids as potent anti-inflammatory agents.

A hybrid pharmacophore approach is used to design and synthesize two novel series of 2'-hydroxychalcone-triazole hybrid molecules 6a-j and 8a-j. These compounds were fully characterized by spectral and elemental analyses. They were evaluated in vitro and in vivo for anti-inflammatory activity.

Conjugation of 4-aminosalicylate with thiazolinones afforded non-cytotoxic potent in vitro and in vivo anti-inflammatory hybrids.

Eicosanoids like leukotrienes and prostaglandins that produced within the arachidonic acid cascade are involved in the pathogenesis of pain, acute and chronic inflammatory diseases. A promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Aiming to develop balanced COX/LOX inhibitors; 4-aminosalicylate based thiazolinones having different substituents at the 5th position of the 4-thiazolinone ring (2-22) were designed, synthesized, characterized and evaluated in vitro and in vivo for their anti-inflammatory activity.

Stereoselective trimethylsilylation of α- and β-galactopyranoses.

Trimethylsilylation of the anomeric hydroxyl groups of tetra-O-benzyl and tetra-O-acetyl galactopyranoses was investigated. Stereoselective formation of β-trimethylsilyl glycoside (β-TMS glycoside) of benzyl protected compound was achieved using N-trimethylsilyl diethylamine. In the course of the investigation of the selective synthesis of TMS galactosides using TMS-imidazole, we observed the formation of an intermediate, which was converted predominantly into α-TMS glycoside after silica gel column chromatography.

Synthesis, biological evaluation and docking study of 1,3,4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX.

Selective inhibition of both cyclooxygenase-2 (COX-2) and 15-lipooxygenase (15-LOX) may provide good strategy for alleviation of inflammatory disorders while minimizing side effects associated with current anti-inflammatory drugs. The present study describes the synthesis, full characterization and biological evaluation of a series of thiadiazole-thiazolidinone hybrids bearing 5-alk/arylidene as dual inhibitors of these enzymes. Our design was based on merging pharmacophores that exhibit portent anti-inflammatory activities in one molecular frame.

Inhibition of SHP2 by new compounds induces differential effects on RAS/RAF/ERK and PI3K/AKT pathways in different cancer cell types.

Kinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers.

CD22-Binding Synthetic Sialosides Regulate B Lymphocyte Proliferation Through CD22 Ligand-Dependent and Independent Pathways, and Enhance Antibody Production in Mice.

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are expressed in various immune cells and most of them carry signaling functions. High-affinity synthetic sialoside ligands have been developed for various Siglecs. Therapeutic potentials of the nanoparticles and compounds that contain multiple numbers of these sialosides and other reagents such as toxins and antigens have been demonstrated.

Novel N-substituted 5-aminosalicylamides as dual inhibitors of cyclooxygenase and 5-lipoxygenase enzymes: Synthesis, biological evaluation and docking study.

Three new series of 5-aminosalicylic acid derivatives; series I (14, 16-18), series II (19-30) and series III (31-41) were synthesized as potential dual COX-2/5-LOX inhibitors. Their chemical structures were confirmed using spectroscopic tools including IR, H NMR, C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity for all target compounds was evaluated in vivo using carrageenan-induced paw edema.

Proximity labeling of cis-ligands of CD22/Siglec-2 reveals stepwise α2,6 sialic acid-dependent and -independent interactions.

Lectins expressed on the cell surface are often bound and regulated by the membrane molecules containing the glycan ligands on the same cell (cis-ligands). However, molecular nature and function of cis-ligands are generally poorly understood partly because of weak interaction between lectins and glycan ligands. Cis-ligands are most extensively studied in CD22 (also known as Siglec-2), an inhibitory B lymphocyte receptor specifically recognizing α2,6 sialic acids.

Synthesis and anti-mycobacterial activity of 4-(4-phenyl-1H-1,2,3-triazol-1-yl)salicylhydrazones: revitalizing an old drug.

The antitubercular drug; para-aminosalicylic acid (PAS) was used as the core scaffold for the design of a series of 1H-1,2,3-triazolylsalicylhydrazones upon coupling with triazole and arylhydrazone moietis to furnish a single molecular architecture. The obtained derivatives were screened against Mycobacterium tuberculosis H37Rv revealing good to high activity for the active compounds (MIC values of 0.39-1.

Nature-inspired design of tetraindoles: Optimization of the core structure and evaluation of structure-activity relationship.

Building on the initial successful optimization of a novel series of tetraindoles, a second generation of the compounds with changes in the core phenyl ring was synthesized to improve anticancer properties. 17 new compounds with different rigidity, planarity, symmetry and degree of conjugation of their core structures to 5-hydroxyindole units were synthesized. All the compounds were fully characterized and tested against breast cancer cell line (MDA-MB-231).