Sumit S. Chourasiya

Design and synthesis of pyrazole-oxindole conjugates targeting tubulin polymerization as new anticancer agents.

A series of twenty one compounds with pyrazole and oxindole conjugates were synthesized by Knoevenagel condensation and investigated for their antiproliferative activity on different human cancer cell lines. The conjugates are comprised of a four ring scaffold; the structural isomers 12b and 12c possess chloro-substitution in the D ring. Among the congeners 12b, 12c, and 12d manifested significant cytotoxicity and inhibited tubulin assembly. Treatments with 12b, 12c and 12d resulted in accumulation of cells in G2/M phase, disruption of microtubule network, and increase in cyclin B1 protein. Zebrafish screening revealed that 12b, and 12d caused developmental defects. Docking analysis demonstrated that the congeners occupy the colchicine binding pocket of tubulin.

Synthesis of imidazo[2,1-b][1,3,4]thiadiazole–chalcones as apoptosis inducing anticancer agents

A series of new imidazo[2,1-b][1,3,4]thiadiazole–chalcones were synthesized by Claisen–Schmidt condensation and evaluated for their cytotoxic activity against various human cancer cell lines. These compounds showed moderate to appreciable antiproliferative activities. Interestingly, compounds like 11a and 11b exhibited significant cytotoxic activity with IC50 values ranging from 0.65 to 2.25 μM in certain cancer cell lines. The structure–activity relationship (SAR) studies reveal that 3,4,5-trimethoxy group containing compounds showed superior cytotoxic activity against selected cancer cell lines compared to other chalcones. These compounds showed G0/G1 phase arrest, apart from activation of caspase-3 and 8 in DU-145 cells. The growth inhibitory effect of these compounds was associated with a decrease in cell cycle regulatory protein cyclin D1 and increase in cyclin dependent kinase inhibitors like Cip1/p21 and Kip1/p27.

Azine-Hydrazone Tautomerism of Guanylhydrazones: Evidence for the Preference Toward the Azine Tautomer

Guanylhydrazones have been known for a long time and have wide applications in organic synthesis, medicinal chemistry, and material science; however, little attention has been paid toward their electronic and structural properties. Quantum chemical analysis on several therapeutically important guanylhydrazones indicated that all of them prefer the azine tautomeric state (by about 3-12 kcal/mol). A set of simple and conjugated azines were designed using quantum chemical methods, whose tautomeric preference toward the azine tautomer is in the range of 3-8 kcal/mol. Twenty new azines were synthesized and isolated in their neutral state. Variable temperature NMR study suggests existence of the azine tautomer even at higher temperatures with no traces of the hydrazone tautomer. The crystal structures of two representative compounds confirmed that the title compounds prefer to exist in their azine tautomeric form.

Azine or hydrazone? The dilemma in amidinohydrazones

Azines belong to an important class of compounds that are found to have numerous applications in medicinal chemistry. Hydrazones are related to azines and are more widely known compounds that carry many biochemical applications. Hydrazones with appropriate substituents can show azine–hydrazone tautomerism. There are many cases in which azines are wrongly considered to be hydrazones. In this article, we report the tautomeric energy differences of azine and hydrazone and provide the structural details of amidinohydrazones, which prefer azine structure rather than that of hydrazone structure, an important example being the anti-hypertensive drug, guanabenz. The importance of appropriate tautomeric representation of guanabenz has been established in terms of its molecular interactions with a known enzyme.

Design, synthesis and biological evaluation of novel unsymmetrical azines as quorum sensing inhibitors

Targeting quorum sensing signals using quorum sensing inhibitors has opened new avenues for the application of known antibiotics. In this context, twenty five unsymmetrical azines were synthesised and evaluated as quorum sensing inhibitors. An efficient one-pot procedure was adopted that directly links 3-methyl-2-(methylthio)benzo[d]thiazol-3-ium salt, hydrazine hydrate and substituted aldehyde to give the designed compounds. The synthesized compounds were preliminarily tested for their potential to inhibit CviR receptor based QS signals in Chromobacterium violaceum. The bioassay screening results suggested that two compounds exhibited potent QS inhibition activity against CviR receptor, showing violacein inhibition (>50%) at 200 μM. Further, the putative positive hits were checked for their potential to inhibit LasR receptor-based QS using the PlasB-gfp(ASV) biomonitor strain of Pseudomonas aeruginosa. These compounds were found to inhibit the QS-mediated GFP signals in a dose dependant manner. Two active compounds also exhibited biofilm clearance at 50 μM concentration. Docking studies were performed to examine their potential to bind to the LasR protein of Pseudomonas aeruginosa.

Sulfonamide vs. sulfonimide: tautomerism and electronic structure analysis of N-heterocyclic arenesulfonamides

A systematic study of the structure and electronic properties of N-heterocyclic arenesulfonamides (NHAS) was performed using experimental and theoretical methods. Ten new examples of NHAS with pyridine and thiazole N-heterocycles were synthesized. X-ray diffraction studies on one of the compounds suggested that the sulfonimide form is preferred; the molecule exists as a dimer due to two strong intermolecular hydrogen bonds. The possibility of sulfonamide (N-sulfonylamine) sulfonimide (N-sulfonylimine) tautomerism was explored using density functional theory (DFT) methods. The energy difference between the two tautomers was small (<6 kcal mol−1) in the gas phase, favoring the sulfonamide tautomer; however, with an increase in the polarity of the solvent, the preference towards the sulfonimide tautomers increased in many examples. Electronic structural analysis of the sulfonimide tautomers suggested the possibility of an unusual (NHC) → N coordination.

Synthesis of 2-anilinopyridine–arylpropenone conjugates as tubulin inhibitors and apoptotic inducers

A series of new (Z)-3-(arylamino)-1-(2-(arylamino)pyridin-3-yl)prop-2-en-1-one conjugates 9a–p were synthesized and evaluated for their cytotoxic activity against some human cancer cell lines. Some of the treated compounds like 9a, 9g and 9j showed significant activity with IC50 values ranging from 0.51 to 1.29 μM. Flow cytometry results revealed that for A549 cells these compounds caused accumulation of cells in the G2/M phase. Interestingly, compound 9a demonstrated a considerable inhibitory effect on tubulin polymerization and showed significant inhibition of tubulin polymerization with an IC50 value of 1.34 μM, whereas nocodazole showed antitubulin activity with an IC50 value 2.64 μM. Further, Hoechst staining and activation of caspase-3 suggested that these conjugates induced cell death by apoptosis. Fluorescence based competitive colchicine binding assay and docking studies suggest that these conjugates 9a and 9g bind to the tubulin perfectly at the colchicine binding site.

Rationalization of Benzazole-2-carboxylate versus Benzazine-3-one/Benzazine-2,3-dione Selectivity Switch during Cyclocondensation of 2-Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous Medium

The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as ethyl glyoxalate and diethyl oxalate in aqueous medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwins rule. On the other hand, the reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with Baldwins rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chemical calculations (density functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates versus benzazine-3-ones/benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier.