Ali Nakhi

AlCl3-mediated hydroarylation–heteroarylation in a single pot: a direct access to densely functionalized olefins of pharmacological interest

An unprecedented AlCl3-mediated method has been developed involving aromatic C-H bond addition to an alkyne and heteroarylation of an arene in a single pot leading to densely functionalized novel olefins, e.g. 2-(2,2-diarylvinyl)-3-arylquinoxalines, as potential inhibitors of sirtuins.

A new route to indoles via in situ desilylation–Sonogashira strategy: identification of novel small molecules as potential anti-tuberculosis agents

A new Pd/C-mediated tandem reaction has been developed for the one pot synthesis of indoles containing an o-(RSO2NH)C6H4 group at the C-2 position. The methodology provided novel indoles as inhibitors of Mycobacterium tuberculosis H37Rv chorismate mutasein vitro representing the first example of chorismate mutase inhibition by a heteroarene based small molecule.

Thieno[3,2-c]pyran-4-one based novel small molecules: their synthesis, crystal structure analysis and in vitro evaluation as potential anticancer agents.

Novel thieno[3,2-c]pyran-4-one based small molecules were designed as potential anticancer agents. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of few steps such as Gewald reaction, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of thiophene ring followed by the fused pyranone moiety and then functionalization at C-7 position of the resultant thieno[3,2-c]pyran-4-one framework. Some of the compounds synthesized showed selective growth inhibition of cancer cells in vitro among which two compounds for example, 5d and 6c showed IC(50) values in the range of 2.0-2.5 μM. The crystal structure analysis of an active compound along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.

Pyrrolo[2,3-b]quinoxalines as inhibitors of firefly luciferase: Their Cu-mediated synthesis and evaluation as false positives in a reporter gene assay

2-Substituted pyrrolo[2,3-b]quinoxalines having free NH were prepared directly from 3-alkynyl-2-chloroquinoxalines in a single pot by using readily available and inexpensive methane sulfonamide (or p-toluene sulfonamide) as an ammonia surrogate. The reaction proceeded in the presence of Cu(OAc)(2) affording the desired product in moderate yield. The crystal structure analysis of a representative compound and its supramolecular interactions are presented. Some of the compounds synthesized exhibited inhibitory activities against luciferase that was supported by the predictive binding mode of these compounds with luciferase enzyme through molecular docking studies. The key observations disclosed here can alert users of luciferase reporter gene assays for possible false positive results due to the direct inhibition of luciferase.

Amberlite IR-120H catalyzed MCR: Design, synthesis and crystal structure analysis of 1,8-dioxodecahydroacridines as potential inhibitors of sirtuins

A rapid, inexpensive and high yielding method has been developed for the synthesis of 1,8-dioxodecahydroacridines using Amberlite IR-120H as a reusable catalyst under open air. These compounds were designed as potential inhibitors of sirtuins and prepared via the MCR of 5,5-dimethyl-1,3-cyclohexanedione, (hetero)aryl aldehydes and (hetero)aromatic amines under mild conditions. Further structure elaboration of a representative compound was performed via Pd catalyzed C-C bond forming reactions. The crystal structure analysis and H-bonding patterns along with in vitro inhibitory activity against yeast Sir2 of the same compound is presented. Docking studies indicated that the compound interacts well with the yeast Sir2.

NaSH in the construction of thiophene ring fused with N-heterocycles: A rapid and inexpensive synthesis of novel small molecules as potential inducers of apoptosis

A facile construction of a thiophene ring fused with N-heterocycles has been achieved via the reaction of NaSH with 2-chloro-3-alkynyl quinoxalines/pyrazines leading to novel 2-substituted thieno[2,3-b]pyrazine/quinoxaline derivatives as potential inducers of apoptosis. Some of them showed encouraging pharmacological properties when tested in zebrafish.

Construction and functionalization of pyranone ring fused with pyran moiety: Design and synthesis of novel pyrano[4,3-b]pyran-5(4H)-ones as potential inhibitors of sirtuins

Novel pyrano[4,3-b]pyran-5(4H)-one based small molecules were designed as potential inhibitors of sirtuins (i.e., yeast sir2, a homolog of human SIRT1). Elegant synthesis of these compounds was performed via a multi-step sequence consisting of MCR, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of a pyran ring followed by the fused pyranone moiety and subsequent functionalization at C-8 position of the resultant core pyrano[4,3-b]pyran-5(4H)-one framework. The crystal structure analysis of a representative iodolactonized product (6d) is presented. Some of the synthesized compounds showed promising inhibitory activities when tested against yeast sir2 in vitro. The compound 6g showed dose dependent inhibition (IC50=78.05μM) of yeast sir2 and good interactions with this protein in silico.

A metal catalyst-free and one-pot synthesis of (3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol derivatives in water

A robust and metal catalyst-free method has been developed for the general and green synthesis of racemic (3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol derivatives. This simple, mild and practical method involves the reaction of 2-aminophenols with (±)-epichlorohydrin in the presence of NaOH in water at room temperature. The reaction features high regioselectivity and a good substrate scope to produce both N-substituted and N-unsubstituted products.