22816-60-0

Usage

Uses

MreB Perturbing Compound A22 is an isothiourea that reversibly perturbs MreB function.

Biochem/physiol Actions

A22 is an inhibitor of MreB, an actin-like bacterial protein, and has been shown to act as an antiobiotic adjuvant. A22 inhibition of MreB disrupts the bacterial actin cytoskeleton, which can cause an increase in cell permeability and altered transport. A22 has been shown to have synergistic effects with several antibiotics including novobiocin and rifampin in gram negative bacteria.

InChI:InChI=1/C8H8Cl2N2S/c9-6-2-1-5(3-7(6)10)4-13-8(11)12/h1-3H,4H2,(H3,11,12)

Upstream product

• 102-47-6 3,4-Dichlorophenylmethyl chloride 
• 17356-08-0 thiourea 

Downstream Products

• 85952-30-3 [(3,4-dichlorophenyl)-methyl]sulfonyl chloride 
• 680221-27-6 5-chloro-3-(3,4-dichlorobenzyl)thio-1,2,4-thiadiazole 
• 36480-40-7 3,4-dichlorobenzyl mercaptan 

Relevant academic research and scientific papers

Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction

In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.

Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA

The discovery of novel small molecules that function as antibacterial agents or cellular probes of biology is hindered by our limited understanding of bacterial physiology and our ability to assign mechanism of action. We previously employed a chemical genomic strategy to identify a novel small molecule, MAC13243, as a likely inhibitor of the bacterial lipoprotein targeting chaperone, LolA. Here, we report on the degradation of MAC13243 into the active species, S-(4-chlorobenzyl)isothiourea. Analogs of this compound (e.g., A22) have previously been characterized as inhibitors of the bacterial actin-like protein, MreB. Herein, we demonstrate that the antibacterial activity of MAC13243 and the thiourea compounds are similar; these activities are suppressed or sensitized in response to increases or decreases of LolA copy number, respectively. We provide STD NMR data which confirms a physical interaction between LolA and the thiourea degradation product of MAC13243, with a K d of ～150 μM. Taken together, we conclude that the thiourea series of compounds share a similar cellular mechanism that includes interaction with LolA in addition to the well-characterized target MreB.

Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives

The reaction of substituted benzylhalides, or of halomethyl derivatives of thiophene or furane, with thiourea or its derivatives yielded the respective isothioureas as hydrohalide salts. The products (a total of 17, including 16 novel compounds) were test

INHIBITION OF CELL PROLIFERATION

The disclosed modulators of Rb:Raf-1 interactions are potent, selective disruptors of Rb:Raf-1 binding, with IC50 values ranging from 80 nM to 500 nM. Further, these compounds are surprisingly effective in inhibiting a wide variety of cancer cells, including osteosarcoma, epithelial lung carcinoma, non small cell lung carcinoma, three different pancreatic cancer cell lines, two different glioblastoma cell lines, metastatic breast cancer, melanoma, and prostate cancer. Moreover, the disclosed compounds effectively disrupt angiogenesis and significantly inhibited tumors in nude mice derived from human epithelial lung carcinoma tumors. Accordingly, the disclosed compounds, pharmaceutical compositions comprising the compounds, methods of inhibiting cell proliferation, methods of treating subjects with cancer, and methods of preparing the disclosed compounds are provided.