One-Pot Green Synthesis and Biological Evaluation of Dimedone-Coupled 2,3-Dihydrofuran Derivatives to Divulge Their Inhibition Potential against Staphylococcal Thioredoxin Reductase Enzyme.

New therapeutic leads are in global demand against multiple drug-resistant , as presently there is no drug of choice left to treat this pathogen. In the present work, we have designed, synthesized, and in vitro validated dimedone-coupled 2,3-dihydrofuran (DDHF)-based inhibitor scaffolds against Staphylococcal thioredoxin reductase (SaTR), a pivotal drug target enzyme of Gram-positive pathogens. Accordingly, a green multicomponent method that is both efficient and one pot has been optimized to synthesize DDHF derivatives.

Synthesis of indol-3-yl-benzofurans and carbazoles Cu(OTf)-catalyzed [3 + 2] and [4 + 2] cycloaddition.

An efficient Cu(OTf)-catalyzed [3 + 2] cycloaddition of indole-3-acrylate with -benzoquinone has been developed to construct two distinct indole-tethered benzofuran scaffolds, offering the first-ever selective access to these scaffolds. Moreover, the [4 + 2] cycloaddition reaction of indole-3-acrylate with vinyl ketone derivatives was used to synthesize carbazoles in a one-pot manner. The disclosed strategies provided a series of selective transformations under low-catalyst loading, with a broad substrate scope featuring diverse applicability and practical simplicity of the developed protocol with easily available substrates.

The rapid construction and biological evaluation of densely substituted pyrrolo[1,2-]indoles a BF·OEt-assisted cascade approach.

Lewis-acid cascade reactions promoted by BF·OEt are reported for the synthesis of highly substituted pyrrolo[1,2-]indoles and congeners of benzofuro[2,3-]indoles. These reactions are highly regio- and diastereoselective towards generating up to five contiguous stereogenic centers, including two vicinal quaternary centers. Furthermore, an established cascade approach and the mechanism proposed herein are well supported by quantum chemistry calculations.

[RhCp*Cl]-Catalyzed Indole Functionalization: Synthesis of Bioinspired Indole-Fused Polycycles.

Polycyclic fused indoles are ubiquitous in natural products and pharmaceuticals due to their immense structural diversity and biological inference, making them suitable for charting broader chemical space. Indole-based polycycles continue to be fascinating as well as challenging targets for synthetic fabrication because of their characteristic structural frameworks possessing biologically intriguing compounds of both natural and synthetic origin. As a result, an assortment of new chemical processes and catalytic routes has been established to provide unified access to these skeletons in a very efficient and selective manner.

A Catecholaldimine-Based Ni-Complex as an Effective Catalyst for the Direct Conversion of Alcohols to -Cinnamonitriles and Aldehydes.

A nickel(II) complex [Ni(HL)] was synthesized by treatment of a new catecholaldimine-based ligand with NiCl·6HO in methanol at room temperature. Complex showed excellent catalytic activity where aromatic and heterocyclic alcohols were rapidly converted into -cinnamonitrile in a one-pot manner via oxidative olefination in the presence of KOH. The potential of the disclosed catalyst and the results obtained for the direct conversion of alcohols to two different functionalities (-cinnamonitrile and aldehydes) are well supported by DFT studies.

Design, Synthesis, and Applications of a Vanadium Complex: An Effective Catalyst for the Direct Conversion of Alcohols and Aldehydes to Esters.

A novel bench-stable V-catalyst [(L)VO](ClO) was synthesized and characterized by X-ray diffraction (XRD) analysis and FT-IR, UV-visible, and EPR spectroscopies, which confirmed its excellent catalytic activity. In application, aldehydes are rapidly converted into their corresponding esters without additives in a one-pot manner using a newly developed catalyst [(L)VO](ClO) and HO as a green oxidant. The developed method is compatible with a broad range of densely substituted aldehydes and allows for the facile preparation of aliphatic, aromatic, and heterocyclic esters, including esters derived from CDOD, methanol, ethanol, -propanol, -butanol, -butyl alcohol, and propargylic alcohol.

Effective Synthesis and Biological Evaluation of Functionalized 2,3-Dihydrofuro[3,2-]coumarins via an Imidazole-Catalyzed Green Multicomponent Approach.

For the first time, an eco-friendly and efficient one-pot green multicomponent approach has been described to synthesize functionalized -2,3-dihydrofuro[3,2-]coumarins (DHFCs). In this synthesis, imidazole and water were used as the catalyst and solvent, respectively, under mild conditions. Applications of the developed catalytic process in a water medium revealed the outstanding activity, productivity, and broad functional group tolerance, affording a series of newly designed DHFC and derivatives in excellent yields (72-98%).

Recent advances in cascade reactions and their mechanistic insights: a concise strategy to synthesize complex natural products and organic scaffolds.

The beauty of cascade reactions to bestow us with cumbersome organic scaffolds has made them a cutting-edge area of research. Although the planning of cascades may require intuition, their results can be highly impactful. The development of cascades to provide specific targeted molecules of an appropriate structural and stereochemical framework poses a significant challenge but can serve as one of the most impressive tools in organic synthesis.

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

An ecofriendly, inexpensive, and efficient route for synthesizing 3,3'-bis(indolyl)methanes (BIMs) and their derivatives was carried out by an electrophilic substitution reaction of indole with structurally divergent aldehydes and ketones using taurine and water as a green catalyst and solvent, respectively, under sonication conditions. Using water as the only solvent, the catalytic process demonstrated outstanding activity, productivity, and broad functional group tolerance, affording the required BIM natural products and derivatives in excellent yields (59-90%). Furthermore, in silico based structure activity analysis of the synthesized BIM derivatives divulges their potential ability to bind antineoplastic drug target and spindle motor protein kinesin Eg5.

Designing a Redox Noninnocent Phenalenyl-Based Copper(II) Complex: An Autotandem Catalyst for the Selective Oxidation of Polycyclic Aromatic Hydrocarbons (PAHs).

A square-planar [CuL] complex , based on the redox-active phenalenyl unit LH = 9,9'-(ethane-1,2-diylbis(azanediyl))bis(1-phenalen-1-one), is prepared and structurally characterized by single-crystal X-ray diffraction analysis. Complex crystallizes at room temperature with the 1 space group. The molecular structure of reveals the presence of intriguing C-H···Cu intermolecular anagostic interactions of the order ∼2.

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

An efficient taurine-catalyzed green multicomponent approach has been described for the first time to synthesize densely substituted therapeutic core dihydropyrano[2,3-]pyrazoles. Applications of the developed synthetic strategies and technologies revealed the synthesis of a series of newly designed 1,4-dihydropyrano[2,3-]pyrazoles containing isonicotinamide, spirooxindole, and indole moieties. Detailed 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 strains.

Design, Synthesis, and Biological Evaluation of Tubulysin Analogues, Linker-Drugs, and Antibody-Drug Conjugates, Insights into Structure-Activity Relationships, and Tubulysin-Tubulin Binding Derived from X-ray Crystallographic Analysis.

Molecular design, synthesis, and biological evaluation of tubulysin analogues, linker-drugs, and antibody-drug conjugates are described. Among the new discoveries reported is the identification of new potent analogues within the tubulysin family that carry a C11 alkyl ether substituent, rather than the usual ester structural motif at that position, a fact that endows the former with higher plasma stability than that of the latter. Also described herein are X-ray crystallographic analysis studies of two tubulin-tubulysin complexes formed within the α/β interface between two tubulin heterodimers and two highly potent tubulysin analogues, one of which exhibited a different binding mode to the one previously reported for tubulysin M.

Improved Total Synthesis of Tubulysins and Design, Synthesis, and Biological Evaluation of New Tubulysins with Highly Potent Cytotoxicities against Cancer Cells as Potential Payloads for Antibody-Drug Conjugates.

Improved, streamlined total syntheses of natural tubulysins such as V (Tb45) and U (Tb46) and pretubulysin D (PTb-D43), and their application to the synthesis of designed tubulysin analogues (Tb44, PTb-D42, PTb-D47-PTb-D49, and Tb50-Tb120), are described. Cytotoxicity evaluation of the synthesized compounds against certain cancer cell lines revealed a number of novel analogues with exceptional potencies [e.g.

Streamlined Total Synthesis of Trioxacarcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxacarcin Analogues.

A streamlined total synthesis of the naturally occurring antitumor agents trioxacarcins is described, along with its application to the construction of a series of designed analogues of these complex natural products. Biological evaluation of the synthesized compounds revealed a number of highly potent, and yet structurally simpler, compounds that are effective against certain cancer cell lines, including a drug-resistant line. A novel one-step synthesis of anthraquinones and chloro anthraquinones from simple ketone precursors and phenylselenyl chloride is also described.

Conformational Study and Vibrational Spectroscopic (FT-IR and FT-Raman) Analysis of an Alkaloid-Borreverine Derivative.

In the present work, structural and spectroscopic investigations were carried out on a borreverine derivative. Borreverine is a class of alkaloid as well a natural antimalarial drug extracted from Borreria verticillata. With the aim of finding possible conformers, a detailed conformational analysis of a borreverine derivative was conducted utilizing density functional theory employing the B3LYP/6-31G(d,p) method.

Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins.

A streamlined total synthesis of N(14)-desacetoxytubulysin H (Tb1) based on a C-H activation strategy and a short total synthesis of pretubulysin D (PTb-D43) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (Tb2-Tb41 and PTb-D42) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.

Protecting group free enantiospecific total syntheses of structurally diverse natural products of the tetrahydrocannabinoid family.

A simple, highly diastereoselective, Lewis acid catalyzed Friedel-Crafts coupling of a cyclic allylic alcohol with resorcinol derivatives has been developed. The method was applied for the enantiospecific total syntheses of structurally diverse natural products such as machaeriol-D, Δ(8)-THC, Δ(9)-THC, epi-perrottetinene and their analogues. Synthesis of both natural products and their enantiomers has been achieved with high atom economy, in a protecting group free manner and in less than 6 steps, the longest linear sequence, in a very good overall yield starting from R-(+) and S-(-)-limonene.

Remarkable switch of regioselectivity in Diels-Alder reaction: divergent total synthesis of borreverine, caulindoles, and flinderoles.

Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of regioselectivity was observed under thermal conditions, where dimerization occurred around the terminal double bond of the dienophile. This switch of regioselectivity was further exploited for the divergent total synthesis of structurally diverse indole alkaloid natural products.

Biomimetic total syntheses of borreverine and flinderole alkaloids.

Dimeric indole alkaloids represent a structurally unique class of natural products having interesting biological activities. Recently, we reported the first total synthesis of flinderoles B and C, structurally unique and potent antimalarial natural products. Central to the design of the approach and by virtue of a one-pot, acid-catalyzed dimerization reaction, the route also provided total synthesis of the borreverine class of natural products.

Biomimetic total syntheses of flinderoles B and C.

A simple and efficient biomimetic synthesis of pyrrolo[1,2-a]indoles using a highly stereo- and regioselective [3 + 2] reaction cascade was developed and then further applied in the first total synthesis of flinderoles B and C, which proceeded in 17.2% yield over the longest linear sequence of 11 steps.