Sequencing [4 + 1]-Cycloaddition and Aza-Michael Addition Reactions: A Diastereoselective Cascade for the Rapid Access of Pyrido[2′,1′:2,3]/Thiazolo[2′,3′:2,3]imidazo[1,5-a]quinolone Scaffolds as Potential Antibacterial and Anticancer Motifs

Abstract

The design and synthesis of a quality compound library containing a small number of skeletally diverse scaffolds, whose members rapidly deliver new chemical probes active against multiple phenotypes, is paramount in drug discovery. In this context, an efficient one-pot strategy for the synthesis of a mini library of sp 3 -enriched hexahydropyrido[2′,1′:2,3]imidazo[1,5-a]quinolinium and hexahydrothiazolo[2′,3′:2,3]imidazo[1,5-a]quinolinium architectures, is described. This new one-pot method features a combination of Sc(OTf) 3 -catalyzed [4 + 1]-cycloaddition with aza-Michael addition reactions. The cascade results in a rapid and diastereoselective formation of these scaffolds via desymmetrization of the oxidative dearomatization products of phenols. Phenotypic screening of the mini library against multiple drug-resistant bacteria and a panel of cancer cell lines identified potential antibacterial and anticancer lead drug candidates. Further investigation of the anticancer leads, indicated by their activity as tubulin-polymerization inhibitors, represents a promising approach for cancer therapy.

Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment

“…The one-pot syntheses of the required compounds have been detailed elsewhere. , In addition, the starting aldehyde determines the substitution pattern around the final product. For example, the piperidinium derivatives SIMR-1740 and SIMR-1911 and the morpholinium derivatives SIMR-1980, SIMR-2415, SIMR-1416, and SIMR-2418 were prepared according to our previously reported procedure (Table ).…”

Cu(I)‐Catalyzed Microwave‐Assisted Multicomponent Reaction Towards Synthesis of Diverse Fluorescent Quinazolino[4,3‐b]quinazolin‐8‐ones and Their Photophysical Study

“…Poly aza-heterocycles are privileged structures with diverse distribution in natural alkaloids and synthetic molecules possessing a broad spectrum of pharmacological activities such as antibacterial, [1][2][3] antituberculosis, [4,5] anticancer, [6,7] and antihypertensive. [8] Among the poly aza-heterocycles, quinazolinones represent a prominent class with diverse medicinal properties.…”

Oxidative Cyclization of 4‐(2‐Mercaptophenyl)‐Substituted 4H‐1,2,4‐Triazolium Species to Tricyclic Benzothiazolium Salts

“…[1][2][3][4][5][6] Of particular interest are compounds based on fused heterocyclic scaffolds which exhibit a wide range of biological activity. [7][8][9][10] Among these molecules are several fused nitrogen-and sulfur-containing heterocyclic anti-cancer agents incorporating a (benzo)thiazole fragment, [10][11][12][13][14][15][16][17][18][19][20][21][22] a thiadiazole ring, [23][24][25][26][27][28] or a thiadiazine unit. [27][28][29] The same scaffolds can be found in molecules with antibacterial, antimicrobial and antifungal properties, [22,[30][31][32][33][34][35] prospective therapeutic agents used to treat asthma or chronic obstructive pulmonary disease, [36][37][38] molecules with anti-inflammatory activity, [39] compounds with antidiabetic activity, [40,41] and promising therapeutics to treat Alzheimer's disease…”

“…Among these molecules are several fused nitrogen‐ and sulfur‐containing heterocyclic anti‐cancer agents incorporating a (benzo)thiazole fragment, [10–22] a thiadiazole ring, [23–28] or a thiadiazine unit [27–29] . The same scaffolds can be found in molecules with antibacterial, antimicrobial and antifungal properties, [22,30–35] prospective therapeutic agents used to treat asthma or chronic obstructive pulmonary disease, [36–38] molecules with anti‐inflammatory activity, [39] compounds with antidiabetic activity, [40,41] and promising therapeutics to treat Alzheimer's disease [42–44] or schizophrenia [45] …”