General Ambient Temperature Benzylic Metalations Using Mixed-Metal Li/K-TMP Amide.

Highly regioselective benzylic metalations in hydrocarbon solvent have been achieved at rt and 0 °C using a mixed-metal Li/K-TMP amide comprised of KOtBu, BuLi, and 2,2,6,6,-tetramethylpiperidine (TMP(H)). Mixing of KOtBu, BuLi, and TMP(H) in heptane gave a solution of the base mixture which when used in deuterium labeling experiments confirmed the requirement of the three reagent components for both reactivity and selectivity. The reaction protocol is operationally straightforward and found to be applicable to a broad range of substrates. Upon generation of the metalated products, they are reacted in heptane at ambient temperature in a variety of synthetically useful ways. Illustrated examples include generation of the benzyltrimethylsilanes and α,α-bis(trimethylsilyl)toluenes reagents, which are bench-stable surrogates of benzyl anions and α-silyl carbanions utilized for nucleophilic addition and Peterson olefination reactions. Direct C-C couplings mediated by 1,2-dibromoethane provided entries into bibenzyls and [2.2]metacyclophanes. Comparison of reaction outcomes with the same reactions carried out in THF at -78 °C showed no negative effects for conducting the reactions under these milder more user-friendly conditions.

Stereoselective Peterson olefinations from bench-stable reagents and N-phenyl imines.

The synthesis of bench-stable α,α-bis(trimethylsilyl)toluenes and tris(trimethylsilyl)methane is described and their use in stereoselective Peterson olefinations has been achieved with a wide substrate scope. Product stereoselectivity was poor with carbonyl electrophiles (E/Z ∼1:1 to 4:1) though this was significantly improved by employing the corresponding substituted N-benzylideneaniline (up to 99:1) as an alternative electrophile. The olefination byproduct was identified as N,N-bis(trimethylsilyl)aniline and could be easily separated from product by aqueous acid extraction. Evidence for an autocatalytic cycle has been obtained.

Subtle Mitsunobu couplings under super-heating: the role of high-throughput continuous flow and microwave strategies.

Non-conventional heating techniques, high-throughput microwave-assisted synthesis and continuous flow penetrate almost every scientific field. Mitsunobu coupling is a ubiquitous choice for the dehydrative redox condensation of primary or secondary alcohols with (pro)nucleophiles. The aim of this review is to showcase the ease of subtle Mitsunobu coupling under super-heating. Surprisingly, this strategy is rather non-trivial; considering the sensitivity of reagents, Mitsunobu chemistry is typically performed at lower temperatures or under ambient conditions. In view of the absence of any previous work focusing on this topic, the current review considers the utility of super-heating in fragile Mitsunobu reactions. Therefore, we anticipate that this review will also bridge some of the apparent gaps in the extant literature by specifically describing the advances made by non-conventional heating assisted by microwave or continuous flow in one of the most powerful stereochemical transformations.

Synthesis and binary QSAR study of antitubercular quinolylhydrazides.

In continuation with our previous work in anti-TB research area, in the present study we have demonstrated the structural diversity of quinolylhydrazides as potent anti-tuberculars. The compound library was synthesized by molecular hybridization approach and tested in vitro against Mycobacterium tuberculosis H37Rv strains. Among the designed conjugates, the most promising molecules were found to exhibit 100% Growth Inhibition (GI) at MIC <6.25 µg/mL. Moreover, several analogs in the designed series were also turned out as excellent anti-tuberculars. To probe the structural characteristics influencing on the SAR, the classification model was generated using a binary QSAR approach termed recursive partitioning (RP) analysis. The significant features outlined by the RP model act as a guide in order to design the 'lead' compound.

Evaluation of structurally diverse benzoazepines clubbed with coumarins as Mycobacterium tuberculosis agents.

Tuberculosis caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. In continuation with our anti-tuberculosis research programme, in this work, we have prepared molecularly diverse coumarins clubbed with benzothiazepines as well as its aza-analogues-benzodiazepines by molecular hybridization. The resulting compounds were screened for their M. tuberculosis activity against H(37) Rv strains using microplate alamar blue assay. Among the designed diversity, the compounds 5k, 5n and 5o were found significantly active in primary anti-tuberculosis assay at minimum inhibitory concentration <6.25 µm. Moreover, the IC(50) values of 5k and 5o in level-2 screening were observed as >10 µg/mL and 3.63 µg/mL, respectively. Design and synthesis of more focused library and its three-dimensional quantitative structure activity relationship analysis are underway.

Ruthenium-catalyzed C-H bond arylations of arenes bearing removable directing groups via six-membered ruthenacycles.

Ruthenium-catalyzed direct arylations of phenols bearing removable directing groups were accomplished through carboxylate assistance via six-membered ruthenacycles as key intermediates.

Diversity oriented design of various hydrazides and their in vitro evaluation against Mycobacterium tuberculosis H37Rv strains.

Control and prevention of tuberculosis is a major challenge, as one-third of the world's population is infected with Mycobacterium tuberculosis. The resurgence of tuberculosis and the emergence of multidrug-resistance strains of mycobacteria, necessitate the search for new class of antimycobacterial agents. As a part of investigation of new antitubercular agents in this laboratory, we describe the syntheses of various hydrazides of comarins, quinolones and pyrroles and screening against M. tuberculosis (Mtb) H37(Rv) by using rifampin as a standard drug. Among the designed molecules, the most prominent compounds 2a-g, 4a and 9a showed >90% GI at MIC<6.25 µg/mL. Finally, these studies suggests that compounds 2a-g, 4a and 9a may serve as promising lead scaffolds for further generation of new anti-TB agents.

Screening for in vitro antimycobacterial activity and three-dimensional quantitative structure-activity relationship (3D-QSAR) study of 4-(arylamino)coumarin derivatives.

The resurgence of tuberculosis and the emergence of multidrug-resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We have synthesized a small library of 50 analogues of 4-(arylamino)coumarins with various aromatic amines at the C(4) - position of the coumarin scaffold. The compounds were evaluated for antimycobacterial activity against Mycobacterium tuberculosis H(37) Rv with rifampicin as the standard. Of the molecules synthesized, compound 9 was found to be most potent with a minimum inhibitory concentration >6.25 µg/mL for 100% inhibition. In an effort to develop new and more effective molecules in this series, the relationship between structure and activity was investigated by comparative molecular field analysis. Various models were generated using comparative molecular field analysis alone and comparative molecular field analysis plus a hydropathy field (HINT). In all, eight models were generated with atom-fit and field-fit alignment strategies. The comparative molecular field analysis models (Models 3a and 4a) based on field-fit alignment were the best with statistically good correlation coefficients (r²) and cross-validated q². The values of r²(pred) for the validation set were 0.469 and 0.516. Based on the comparative molecular field analysis contours, some insights into the structure-activity relationship of the compounds could be gained.

Synthesis, in vitro antitubercular activity and 3D-QSAR study of 1,4-dihydropyridines.

In continuation of our research program on new antitubercular agents, this article is a report of the synthesis of 97 various symmetrical, unsymmetrical, and N-substituted 1,4-dihydropyridines. The synthesized molecules were tested for their activity against M. tuberculosis H (37)Rv strain with rifampin as the standard drug. The percentage inhibition was found in the range 3-93%. In an effort to understand the relationship between structure and activity, 3D-QSAR studies were also carried out on a subset that is representative of the molecules synthesized. For the generation of the QSAR models, a training set of 35 diverse molecules representing the synthesized molecules was utilized. The molecules were aligned using the atom-fit technique. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r (2)) of 0.98 and 0.95 with cross-validated r (2)(q (2)) of 0.56 and 0.62, respectively. The 3D-QSAR models were externally validated against a test set of 19 molecules (aligned previously with the training set) for which the predictive r(2)(r(r)(pred)) is recorded as 0.74 and 0.69 for the CoMFA and CoMSIA models, respectively. The models were checked for chance correlation through y-scrambling. The QSAR models revealed the importance of the conformational flexibility of the substituents in antitubercular activity.

Synthesis of 1-(2,6-dichlorophenyl)-3-methylene-1,3-dihydro-indol-2-one derivatives and in vitro anticancer evaluation against SW620 colon cancer cell line.

A small library of 2-indolinone derivatives with the 2,6-dichlorophenyl ring at the N(1) position and with varying substitutions including aryl groups at the 3-position were synthesized, and their structures were confirmed by spectral analysis. All molecules were screened for their in vitro cytotoxic activity on SW620 colon cancer cell lines. Among the designed series compounds 4c, 4f and 4j were found to be active at concentrations of 2-15 microg/ml. Some 3D-QSAR models were also built to understand the structure-activity relationship.

1,5-Benzothiazepine, a versatile pharmacophore: a review.

1,5-Benzothiazepine and 1,5-benzodiazipine are the two main seven-membered heterocyclic ring systems reported for their cardiac and psychotherapeutic activities. Successful introduction of diltiazem and clentiazem for angina pectoris, hypertension, arrhythmias and other related cardiac disorders proved potential of 1,5-benzothiazepine moiety. Subsequently 1,5-benzodiazepines were highlighted as important biologically active scaffolds. Also, discovery of thiazesim and quetiapine fumarate as psychotropic agents attracted much attention worldwide. The current review article focuses on pharmacological profile associated with 1,5-benzodiazepines. This article mainly covers structural modifications done for various targets along with the brief description of the targets.

Synthesis, anti-tubercular activity and 3D-QSAR study of coumarin-4-acetic acid benzylidene hydrazides.

A set of 25 coumarin-4-acetic acid benzylidene hydrazides were synthesized and characterized by NMR, IR and mass spectroscopic techniques. The compounds were evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H(37)Rv strain using the BACTEC 460 system to determine percentage inhibition. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field Analysis (CoMFA). Several statistically significant CoMFA models were generated. The CoMFA model generated with database alignment was the best in terms of overall statistics. The CoMFA contours provide a good insight into the structure activity relationships of the compounds reported herein.