Design, Synthesis, and Biological Evaluation of Densely Substituted Dihydropyrano[2,3-c]pyrazolesviaa Taurine-Catalyzed Green Multicomponent Approach

Abstract

An efficient taurine-catalyzed green multicomponent approach has been described for the first time to synthesize densely substituted therapeutic core dihydropyrano­[2,3-c]­pyrazoles. Applications of the developed synthetic strategies and technologies revealed the synthesis of a series of newly designed 1,4-dihydropyrano­[2,3-c]­pyrazoles containing isonicotinamide, spirooxindole, and indole moieties. Detailed in silico analysis of the synthesized analogues revealed their potential to bind wild-type and antibiotic-resistant variants of dihydrofolate reductase, a principal drug target enzyme for emerging antibiotic-resistant pathogenic Staphylococcus aureus strains. Hence, the synthesized dihydropyrano­[2,3-c]­pyrazole derivatives presented herein hold immense promise to develop future antistaphylococcal therapeutic agents.

Effective Synthesis and Biological Evaluation of Natural and Designed Bis(indolyl)methanes via Taurine-Catalyzed Green Approach

“…Being inspired by the green approach of BIMs synthesis methodology, and our recent report on the taurine-catalyzed multicomponent reaction for the synthesis of densely substituted dihydropyrano[2,3- c ]pyrazoles, 66 we became interested in assessing the efficacy of taurine as a catalyst to boost the multicomponent reaction of probe indole and functionalized aldehyde. In our quest to find a best catalytic condition to access BIMs and their derivatives, the reaction was performed with p -methoxybenzaldehyde 1a and indole 2a as a model substrate under a different set of catalysts and conditions.…”

“… 65 Hence, since the discovery of monastrol site targeting resistance, resistant therapeutic leads are in high demand to confront drug-resistant Eg5 mutations. 66 Interestingly, the synthesized BIM derivatives were found to be recalcitrant toward drug-resistant Eg5 mutations. The detailed structure activity analysis of BIM derivative(s)/Eg5 binding and a plausible molecular mechanism of inhibition are presented herein.…”

Recent Applications of the Multicomponent Synthesis for Bioactive Pyrazole Derivatives

“…Hence, it is an emerging field of study as it relates to a global health challenge, thereby numerous strategies will be required to develop new therapeutic compounds as antibacterial agents. In this regard, the broad-scale pharmaceutical applications of pyrano[2,3- c ]pyrazole, including its appearance in numerous biologically important scaffolds, manifest its significant demand worldwide [ 26 ]. For example, the taurine-catalyzed four-component reaction of diverse (hetaryl)aldehydes 1 , malononitrile 2 , ethyl acetoacetate 3 , and hydrazine hydrate 4 in water at 80 °C for 2 h afforded 1,4-dihydropyrano[2,3- c ]pyrazoles 6 in 85−92% yields ( Scheme 1 ) [ 26 ].…”

“…In this regard, the broad-scale pharmaceutical applications of pyrano[2,3- c ]pyrazole, including its appearance in numerous biologically important scaffolds, manifest its significant demand worldwide [ 26 ]. For example, the taurine-catalyzed four-component reaction of diverse (hetaryl)aldehydes 1 , malononitrile 2 , ethyl acetoacetate 3 , and hydrazine hydrate 4 in water at 80 °C for 2 h afforded 1,4-dihydropyrano[2,3- c ]pyrazoles 6 in 85−92% yields ( Scheme 1 ) [ 26 ]. Under the same optimized conditions, the four-component reaction was extended to isoniazid 5 leading to densely substituted products 7 in 72−97% yields.…”

“…Hydrogen bond formation is indicated by the green dotted line, whereas hydrophobic interactions are indicated by the spiked arcs. Image adapted from Mali et al [ 26 ].…”