Jagadeesh Babu Nanubolu

Access to Imidazo[1,2-a]pyridines via Annulation of α-Keto Vinyl Azides and 2-Aminopyridines

A novel strategy for the synthesis of imidazo[1,2-a]pyridines via efficient catalyst/metal-free annulations of α-keto vinyl azides and 2-aminopyridines is described. Several imidazo[1,2-a]pyridines were synthesized from readily available vinyl azides and 2-aminopyridines and obtained in highly pure form by simply evaporating the reaction solvent. This remarkably high yielding and atom economical protocol allows the formation of three new C-N bonds through cascade reactions and rearrangements.

Synthesis and cytotoxicity evaluation of highly functionalized pyranochromenes and pyranopyrans.

A series of fluorinated tetrahydropyrano[3,2-c]chromenes and dihydropyrano[3,2-b]pyran derivatives have been synthesized and their in vitro cytotoxic activities have been determined in cervical cancer cell line (HeLa), human breast adenocarcinoma cell line (MDA-MB-231 and MCF-7) and human alveolar adenocarcinoma cell line (A549). Compounds 4g, 4k, 4p showed a very potent activity against MDA-MB-231, and 4c, 4p showed promising activity against MCF-7, while compounds 4c, 4g, 4p showed moderate activity against HeLa.

One-pot, three-component approach to the synthesis of 3,4,5-trisubstituted pyrazoles.

An operationally simple and high yielding protocol for the synthesis of polyfunctional pyrazoles has been developed through one-pot, three-component coupling of aldehydes, 1,3-dicarbonyls, and diazo compounds as well as tosyl hydrazones. The reaction proceeds through a tandem Knoevenagel condensation, 1,3-dipolar cycloaddition, and transition metal-free oxidative aromatization reaction sequence utilizing molecular oxygen as a green oxidant. The scope of the reaction was studied by varying the aldehyde, 1,3-dicarbonyl, and diazo component individually.

Synthesis of Alkaloid-Mimicking Tricyclic Skeletons by Diastereo- and Regioselective Ugi/ipso-Cyclization/Aza-Michael Cascade Reaction in One-Pot.

A one-pot process has been developed for preparing alkaloid-like tricyclic skeletons by employing an Ugi reaction, an acid mediated ipso-cyclization and an aza-Michael addition. The transformation is operationally simple and provides products in a diastereo- and regioselective manner with good-to-excellent yields.

Synthesis and biological evaluation of new epalrestat analogues as aldose reductase inhibitors (ARIs).

Baylis-Hillman chemistry derived four series of new epalrestat analogues were synthesized. Three structural changes are introduced in these 39 new epalrestat analogues synthesized. All compounds were evaluated for their in vitro aldose reductase inhibitory (ALR) activity. Biological activity data indicates that compounds 6, 16, 19, 28 and 29 are potent and the activity is in the range of reference drug, epalrestat. Molecular modelling studies were performed to understand the binding interactions of these active molecules with the ALR protein. Molecular docking data indicates the key interactions of epalrestat were retained in some of the active compounds whereas some new interactions were noticed for other molecules. The modifications introduced on epalrestat have impact for developing a new-type of ALR inhibitor.

Visible‐Light/Photoredox‐Mediated sp3 CH Functionalization and Coupling of Secondary Amines with Vinyl Azides in Flow Microreactors

Structurally diverse imidazole derivatives were synthesized by a visible-light/[Ru(bpy)3 ][(PF6 )2 ]-mediated coupling of vinyl azides and secondary amines in flow microreactors. This operationally simple and atom-economical protocol allows the formation of three new C-N bonds through the functionalization of sp(3)  C-H bonds adjacent to the secondary nitrogen atom. In order to get mechanistic insight of the coupling reaction, several control experiments were carried out and discussed.

Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as antimycobacterial agents

A library of novel 3-trifluoromethyl pyrazolo-1,2,3-triazole hybrids (5-7) were accomplished starting from 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (1) via key intermediate 2-azido-N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)acetamide (3) through click chemistry approach. Thus obtained compounds in 5-7 series were evaluated for in vitro antimycobacterial activity against Mycobacterium smegmatis (MC(2) 155) and also verified the cytotoxicity. These studies engendered promising lead compounds 5q, 7b and 7c with MIC (μg/mL) values 15.34, 16.18 and 16.60, respectively. Amongst these three compounds, 2-(4-(4-methoxybenzoyl)-1H-1,2,3-triazol-1-yl)-N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl) acetamide (5q) emerged as the most promising antitubercular agent with lowest cytotoxicity against the A549 cancer cell line. This is the first report to demonstrate the pyrazolo triazole hybrids as potential antimycobacterial agents.

Visible Light Driven Photocascade Catalysis: Ru(bpy)3(PF6)2/TBHP-Mediated Synthesis of Fused β-Carbolines in Batch and Flow Microreactors

1,2,3,4-Tetrahydro-β-carbolines were coupled with α-keto vinyl azides through an unprecedented visible light-Ru(bpy)3(PF6)2/TBHP mediated photocascade strategy that involves photosensitization, photoredox catalysis and [3 + 2] cycloaddition reaction. The scope and scale-up feasibility of the photocascade strategy was demonstrated by synthesizing 18 different fused β-carbolines in moderate to good yields using batch and continuous flow microreactor. This operationally simple synthetic protocol allows the formation of one C-C and two C-N new bonds in the overall transformation.

Group-assisted purification (GAP) chemistry for dihydrofurans: water as a medium for catalyst free synthesis in a one pot four component reaction

A simple, catalyst free, water mediated, one pot four component, green protocol was developed for title compounds 7 starting from aromatic aldehydes (1), malononitrile (2), 1,3-diones (3) and N-chlorosuccinimide (NCS) in a sequential addition reaction at ambient temperature. The approach presented herein, for the first time, is through an unusual rearrangement where NCS was reacted with 2-amino-7,7-dimethyl-5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4), which was formed by the Knoevenagel condensation of aldehyde and malononitrile followed by the Michael addition of 3. In addition, this novel protocol is compatible with various aldehydes and active C–H functional derivatives, accomplishes high yields and follows the GAP chemistry principle. Interestingly, compound 4 when reacted with NCS in alcohol medium gave 2-cyano-6,6-dimethyl-4-oxo-3-aryl-2,3,4,5,6,7-hexahydrobenzofuran-2-carboxylate (5).

Sixth polymorph of aripiprazole - an antipsychotic drug

In the present study we report the existence of sixth polymorph of aripiprazole (APPZ) as characterised by single-crystal X-ray diffraction, and present its structural and lattice energy comparison with five other polymorphs of APPZ in the Cambridge Structural Database (CSD). Incidentally, aripiprazole with six well characterised polymorphs happens to be the second most polymorphic system in the CSD after the classic ROY molecule which has a record number of seven polymorphs. The extensive polymorphism in the title compound is attributed to a very high degree of conformational freedom, significant differences in the hydrogen bonding and due to the influence of crystal packing effects. Further, the stabilisation of a metastable conformer by more efficient crystal packing or a less efficient crystal packing by a more stable conformer are believed to contribute its rich polymorphic behavior. Besides these structural features, an interesting observation noted in APPZ system is that, out of the six polymorphs three polymorphs crystallised in centrosymmetric space groups (all P) and the remaining three are in the non-centrosymmetric space groups (P21, P21 and Pna21). The presence or absence of a specific hydrogen bonding motif in the crystal structure is correlated to the selection of the space group. Overall aripiprazole presents an interesting case study of packing, synthon and conformational polymorphism. The present study indicates the importance of exploring suitable crystallisation conditions for a good polymorph screening in the early stages of the drug development.