Shahnawaz Khan

Metal-Free Oxidative Amidation of 2-Oxoaldehydes: A Facile Access to α-Ketoamides

A novel and efficient method for the synthesis of α-ketoamides, employing a dimethyl sulfoxide (DMSO)-promoted oxidative amidation reaction between 2-oxoaldehydes and amines under metal-free conditions is presented. Furthermore, mechanistic studies supported an iminium ion-based intermediate as a central feature of reaction wherein C1-oxygen atom of α-ketoamides is finally derived from DMSO.

A Ligand-Free Pd-Catalyzed Cascade Reaction: An Access to the Highly Diverse Isoquinolin-1(2H)-one Derivatives via Isocyanide and Ugi-MCR Synthesized Amide Precursors

A novel ligand-free palladium-catalyzed cascade reaction for the synthesis of highly diverse isoquinolin-1(2H)-one derivatives from isocyanide and amide precursors synthesized by Ugi-MCR has been developed. A broad variety of acids, amines, and isocyanides were used as starting materials for Ugi-MCR leading to various amide precursors, which in turn provided entry into diverse isoquinolin-1(2H)-one derivatives. The reaction proceeds through tandem isocyanide insertion with intramolecular cyclization followed by a Mazurciewitcz-Ganesan type sequence to provide isoquinoline-1(2H)-one derivatives in moderate to good yields.

Skeletal Diverse Synthesis of N-Fused Polycyclic Heterocycles via the Sequence of Ugi-Type MCR and CuI-Catalyzed Coupling/Tandem Pictet–Spengler Reaction

Several diversity-oriented syntheses of N-fused polycyclic heterocycles have been demonstrated but most of them are based on point diversity within the same library and usually involve time-consuming sequential multistep syntheses, which also suffer from low yields and/or poor precursor scopes. We have developed a new strategy for the syntheses of skeletal diverse N-fused polycyclic compounds via an Ugi-type MCR followed by a CuI-catalyzed coupling reaction or tandem Pictet-Spengler reaction. This two-step sequence provides eight distinct skeleton of fused {6-5-5-6}, {5-5-5-6}, {6-5-6-6}, and {5-5-6-6} ring systems that have applications in medicinal chemistry and chemical genetics too.

Synthesis and cytotoxicity evaluation of (tetrahydro-β-carboline)-1,3,5-triazine hybrids as anticancer agents

A series of tetrahydro-beta-carbolines and 1,3,5-triazine hybrids have been synthesized and evaluated for their cytotoxicity against a panel of eight human cancer cell lines and normal human fibroblasts (NIH3T3). It led us to discovery of racemic compounds 69, 71 and 75, which are selectively cytotoxic towards KB (oral cancer) cell line with IC50 values of 105.8, 664.7 and 122.2 nM, respectively; while their enantiopure forms are less active and not selective. Enantiopure compound 42 showed 2.5 times more selectivity towards MCF7 cells over normal fibroblast NIH3T3 cells with an IC50 value of 740 nM, also arrests cell cycle in G1 phase and induces apoptosis in MCF7 and MDA MB231 cell lines.

Aminocatalytic Cross‐Coupling Approach via Iminium Ions to Different CC Bonds

Given the attractive ability of iminium ions to functionalize molecules directly at ostensibly unreactive positions, the reactivity of iminium ions, in which an α CH2 group is replaced by CO was explored. Background studies on the ability of such iminium cations to promote reactions via an iminium-catalyzed or iminium-equivalent pathway are apparently unavailable. Previously, tandem cross-coupling reactions were reported, in which an iminium ion undergoes nucleophilic 1,2-addition to give a putative three-component intermediate that abstracts a proton in situ and undergoes self-deamination followed by unprecedented DMSO/aerobic oxidation to generate α-ketoamides. However, later it was observed that iminium ions can generate valuable α-ketoamides through simple aerobic oxidation. In all reactions, iminium ions were generated in situ by reaction of 2-oxoaldehydes with secondary amines.

Synthesis of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-β-carbolines as antileishmanial agents

A series of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-beta-carboline derivatives has been synthesized and evaluated for antileishmanial activity against Leishmania donovani. Compound 8 exhibited best antileishmanial activity with IC(50) value of 1.93 microg/ml against amastigotes, high selectivity index, and was more active than reference drugs sodium stilbogluconate and pentamidine.

Access to Indole- And Pyrrole-Fused Diketopiperazines via Tandem Ugi-4CR/Intramolecular Cyclization and Its Regioselective Ring-Opening by Intermolecular Transamidation

An efficient approach for the synthesis of indole- and pyrrole-fused diketopiperazines has been developed. This protocol involves the Ugi four-component reaction (U-4CR) followed by an intramolecular cyclization of the Ugi products at room temperature to afford the desired products in good to excellent yields. In addition, it is interesting to report the subsequent regioselective ring-opening of diketopiperazine unit occurring via an intermolecular transamidation reaction under mild condition, resulting in the formation of highly functionalized indole-2-carboxamides and pyrrole-2-carboxamides.

A natural product inspired hybrid approach towards the synthesis of novel pentamidine based scaffolds as potential anti-parasitic agents

A natural product inspired molecular hybridization approach led us to a series of novel pentamidine based pyrimidine and chalcone scaffolds. All the hybrids were evaluated for their anti-leishmanial potential. Most of the screened compounds have showed significant in vitro anti-leishmanial activity with less cytotoxicity in comparison to the standard drugs (pentamidine, sodium stibogluconate, and miltefosine). Additionally, anti-malarial screening of these compounds was also done and four compounds have shown superior activity against chloroquine resistance strain (K1) of Plasmodium falciparum.

Diversity-oriented reconstruction of primitive diketopiperazine-fused tetrahydro-β-carboline ring systems via Pictet–Spengler/Ugi-4CR/deprotection-cyclization reactions

An expedient construction of tetrahydro-β-carbolinediketopiperazine ring systems, which are present in various indole alkaloids, is documented. The synthetic strategy proceeds through a Pictet–Spengler reaction followed by an Ugi-4CR and deprotection-cyclization reactions. This is the first report of a Pre-Ugi multicomponent reaction modification using 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylic acid as the acidic partner. This novel approach provides highly diverse reconstructions of novel tetrahydro-β-carbolinediketopiperazine derivatives, which can also be used as privileged structures in medicinal chemistry.

2-Aminoimidazole, Glycociamidine and 2-Thiohydantoin-Marine Alkaloids as Molecular Inspirations for the Development of Lead Structures

This review provides a detailed account on the biological activities of structurally diverse secondary metabolites from marine sponges having 2-aminoimidazole, glycociamidine and/or 2-thiohydantoin ring functions. This review will complement two previous short reviews which did however not address the potential of these natural products for drug discovery. We will discuss the naturally occurring alkaloids and give an account on their structure activity relationships.