Rambabu Gundla

Reagent-Based DOS: Developing a Diastereoselective Methodology to Access Spirocyclic- and Fused Heterocyclic Ring Systems†

Herein, we report a diversity-oriented-synthesis (DOS) approach for the synthesis of biologically relevant molecular scaffolds. Our methodology enables the facile synthesis of fused N-heterocycles, spirooxoindolones, tetrahydroquinolines, and fused N-heterocycles. The two-step sequence starts with a chiral-bicyclic-lactam-directed enolate-addition/substitution step. This step is followed by a ring-closure onto the built-in scaffold electrophile, thereby leading to stereoselective carbocycle- and spirocycle-formation. We used in silico tools to calibrate our compounds with respect to chemical diversity and selected drug-like properties. We evaluated the biological significance of our scaffolds by screening them in two cancer cell-lines. In summary, our DOS methodology affords new, diverse scaffolds, thereby resulting in compounds that may have significance in medicinal chemistry.

Synthesis of privileged scaffolds by using diversity-oriented synthesis.

An elegant reagent-controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. In silico studies were used to estimate the drug-like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14.

Molecular hybrid design, synthesis and biological evaluation of N-phenyl sulfonamide linked N-acyl hydrazone derivatives functioning as COX-2 inhibitors: new anti-inflammatory, anti-oxidant and anti-bacterial agents

Herein, we report the design, synthesis and biological evaluation of the anti-inflammatory activities of N-phenyl sulfonamide linked N-acylhydrazones (NPS–NAH), using the molecular hybridization approach. Hybrid compounds were further validated by theoretical studies. Compound 1f from series-1 and compound 2a from series-2 exhibited strong selective COX-2 enzyme inhibition at IC50 = 8.9 μM and 8.4 μM respectively. Effective in vivo anti-inflammatory profiling of potent and selective COX-2 inhibitors, including compound 1f and 2a was carried out and compared with known COX-2 inhibitors. Subsequently, these compounds were tested for antioxidant activity, and 1h (IC50 = 28.62 μM) from series-1 and compound 2d (IC50 = 25.34 μM) from series-2 were found to be potent anti-oxidants. Additionally, these compounds were screened for antibacterial activity, and compound 1l and 2b exhibited better Gram +ve and −ve anti-bacterial activity than the reference standards, Ciprofloxacin and Norfloxacin. These results validated the idea of exploiting the hybridization strategy for the identification of new N-phenyl sulfonamide–NAH derivatives for optimizing anti-inflammatory, antioxidant and anti-bacterial activities.

A reagent based DOS strategy via Evans chiral auxiliary: highly stereoselective Michael reaction towards optically active quinolizidinones, piperidinones and pyrrolidinones

In the present study, we have demonstrated the diversity oriented synthesis of nitrogen heterocycles viz. chiral piperidinones, quinolizidinones and diaryl pyrrolidinones from Michael adducts generated via a TiCl4-catalyzed highly stereoselective Michael reaction with nitrostyrenes and an Evans chiral auxiliary. We also reported a Cu-4,4’-(isopropyl)-substituted isopropylidene-bridged 2,2’-bis-1,3’-oxazoline catalyst mediated catalytic asymmetric version of this reaction. In silico analysis is utilized to evaluate the diversity of the set of compounds against shape space (PMI), polar surface area (PSA) calculations and relevant drug like properties (viz. HBA, HBD, PSA, mol. wt., log P and log D). Finally, the molecules were screened against microorganisms to assess their antimicrobial properties.

Pyrrolidine and piperidine based chiral spiro and fused scaffolds via build/couple/pair approach

A versatile stereoselective diversity oriented synthetic pathway to the possible spiro and fused diverse heterocyclic small molecules is described. The strategy involved the “build–couple–pair” approach involving an SNAr, Michael addition and Mannich reaction on chiral acyl bicyclic lactams 2a/b, followed by a cyclization onto the inbuilt scaffold electrophile, thereby leading to asymmetric fused and spirocyclic nitrogen heterocycles. A “post-pair” phase has been incorporated to generate more polar compounds. We used Principal Component Analysis (PCA) and polar moment of inertia to evaluate the shape-space diversity of our scaffolds with respect to a commercial database and observed extraordinary diversity within the scaffold network. We further calculated the polar surface area (PSA) of our molecules which is an indicator for drug cell permeability.

Synthesis and biological potentials of some new 1,3,4-oxadiazole analogues

In continuation of our research to explore new antiproliferative agents, we report herein the synthesis and antiproliferative activity of two new series of N-(substituted phenyl)-5-aryl-1,3,4-oxadiazol-2-amine (4a–j) and N-{[5-aryl-1,3,4-oxadiazol-2-yl]methyl}-substituted aniline (4k–t) analogs. The antiproliferative activity of fifteen compounds (4a–h, and 4n) was tested against nine different panels of nearly 60 NCI human cancer cell lines. N-(2-Methoxyphenyl)-5-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine (4b) and 4-{5-[(2-Methoxyphenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (4c) showed maximum antiproliferative activity among the series with a mean growth percents (GPs) of 45.20 and 56.73, respectively. The compound 4b showed significant percent growth inhibitions (GIs) on nearly 47 cancer cell lines and were found to have higher sensitivity towards HL-60(TB), MDA-MB-435, OVCAR-3, and K-562 with percent GIs (GIs) of 109.62, 105.90, 91.94, and 88.30, respectively. Similarly the compound, 4c showed significant percent GIs on nearly 42 cancer cell lines and were found to have higher sensitivity towards UO-31, MDA-MB-435, KM12, and K-562 with %GIs of 84.31, 80.52, 78.65, and 77.06, respectively. Both the compounds 4b and 4c showed better antiproliferative activity than the standard drug Imatinib while the antiproliferative activity of compound 4b was found to be nearly comparable to the standard drug 5-flurouracil (5-FU). The antiproliferative activity of five compounds (4o-s) was tested against the breast cancer cell lines (MCF-7 and MDA-MB-231) as per Sulforhodamine B assay (SRB assay). N-{[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-4-methylaniline (4p) was found to have significant antiproliferative activity against MCF-7 and MDA-MB-231 with GI50 of 12.9 and 59.3 µM, respectively. Further, the free radical scavenging activity results were significant for the most active compounds, 4b (IC50 = 21.07 µM) and 4c (IC50 = 15.58 µM). The docking studies was also carried against tubulin enzyme and the most active compound (4b) showed good interaction with the residues Lys254, Ala250, Cys241, Val318, Ala316, Asn258, and Lys352 present in the hydrophobic cavity of tubulin.

CCDC 1572633: Experimental Crystal Structure Determination

Related Article: Jyoti Chauhan, Tania Luthra, Rambabu Gundla, Antonio Ferraro, Ulrike Holzgrabe, Subhabrata Sen|2017|Org.Biomol.Chem.|15|9108|doi:10.1039/C7OB02230A

CCDC 1572513: Experimental Crystal Structure Determination

Related Article: Jyoti Chauhan, Tania Luthra, Rambabu Gundla, Antonio Ferraro, Ulrike Holzgrabe, Subhabrata Sen|2017|Org.Biomol.Chem.|15|9108|doi:10.1039/C7OB02230A