The latest perspectives of small molecules FMS kinase inhibitors.

FMS kinase is a type III tyrosine kinase receptor that plays a central role in the pathophysiology and management of several diseases, including a range of cancer types, inflammatory disorders, neurodegenerative disorders, and bone disorders among others. In this review, the pathophysiological pathways of FMS kinase in different diseases and the recent developments of its monoclonal antibodies and inhibitors during the last five years are discussed. The biological and biochemical features of these inhibitors, including binding interactions, structure-activity relationships (SAR), selectivity, and potencies are discussed. The focus of this article is on the compounds that are promising leads and undergoing advanced clinical investigations, as well as on those that received FDA approval. In this article, we attempt to classify the reviewed FMS inhibitors according to their core chemical structure including pyridine, pyrrolopyridine, pyrazolopyridine, quinoline, and pyrimidine derivatives.

Complexity-to-Diversity and Pseudo-Natural Product Strategies as Powerful Platforms for Deciphering Next-Generation Therapeutics.

Stereochemical and skeletal complexity are particularly important vis-à-vis the cross-talks between a small molecule and a complementary active site of a biological target. This intricate harmony is known to increase selectivity, reduce toxicity, and increase the success rate in clinical trials. Therefore, the development of novel strategies for establishing underrepresented chemical space that is rich in stereochemical and skeletal diversity is an important milestone in a drug discovery campaign. In this review, we discuss the evolution of interdisciplinary synthetic methodologies utilized in chemical biology and drug discovery that has revolutionized the discovery of first-in-class molecules over the last decade with an emphasis on complexity-to-diversity and pseudo-natural product strategies as a remarkable toolbox for deciphering next-generation therapeutics. We also report how these approaches dramatically revolutionized the discovery of novel chemical probes that target underrepresented biological space. We also highlight selected applications and discuss key opportunities offered by these tools and important synthetic strategies used for the construction of chemical spaces that are rich in skeletal and stereochemical diversity. We also provide insight on how the integration of these protocols has the promise of changing the drug discovery landscape.

Divergent Protocol for the Synthesis of Isoquinolino[1,2-b]quinazolinone and Isoquinolino[2,1-a]quinazolinone Derivatives.

The development of robust and step-economic strategies to access structurally diverse drug-like compound collections remains a challenge. A distinct structural option that constitutes the core scaffold of many biologically significant molecules is the quinazolinone ring system. Several members of this family of privileged substructures have gained attention due to their diverse biological activities. In this context, the development of an efficient strategy for their access is needed. Herein, we report a divergent metal-free operation to access a diverse collection of C6-substituted pyrrolo[4',3',2':4,5]isoquinolino[1,2-b]quinazolin-8(6H)-one and pyrrolo[4',3',2':4,5]isoquinolino[2,1-a]quinazolin-12(6H)-one architectures. The described cascade unites Friedel-Crafts and aza-Michael addition reactions. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the cascade features a promising approach for the design of unique compound libraries for drug design and discovery programs.

Stereodivergent Desymmetrization of Phenols En Route to Modular Access to Densely Functionalized Quinazoline and Oxazine Scaffolds.

The de novo assembly of stereochemically and skeletally diverse scaffolds is a powerful tool for the discovery of novel chemotypes. Hence, the development of modular, step- and atom-economic synthetic methods to access stereochemically and skeletally diverse compound collection is particularly important. Herein, we show a metal-free, stereodivergent build/couple/pair strategy that allows access to a unique collection of benzo[5,6][1,4]oxazino[4,3-a]quinazoline, quinolino[1,2-a]quinazoline and benzo[b]benzo [4,5]imidazo[1,2-d][1,4]oxazine scaffolds with complete diastereocontrol and wide distribution of molecular architectures. This metal-free process proceeds via desymmetrization of phenol derivatives. The cascade unites Mannich with aza-Michael addition reactions, providing expeditious entries to diverse classes of molecular shapes in a single operation.

Design and synthesis of new adamantyl derivatives as promising antiproliferative agents.

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 IC50 values over several cancer cell lines that belong to leukemia and colon cancer such as K-562, RPMI-8226, SR, COLO 205, HCT-116, HCT-15, HT29, KM12, and SW-620 cell lines. Compounds 1e and 1i induced apoptosis in K-562 leukemia cells in a dose-dependent manner. Compound 1i showed the highest cytotoxic activity with IC50 value of 200 nM against HT29 cell line. In addition, compounds 1e and 1i were tested against normal breast cells (HME1) and normal skin fibroblast cells (F180) and the results revealed that the compounds are safe toward normal cells compared to cancers cells. Enzymatic assays against NPP1-3 and carbonic anhydrases II, IX, and XII were performed to investigate the possible molecular target(s) of compounds 1e and 1i. Furthermore, a molecular docking study was performed to predict the binding modes of compounds 1e and 1i in the active site of the most sensitive enzymes subtypes.