Pawan K. Sharma

Synthesis and biological evaluation of some pyrazolylpyrazolines as anti-inflammatory-antimicrobial agents

A new series of pyrazolylpyrazolines (5a-k) was synthesized by the reaction of appropriate chalcones (3a-k) with 4-hydrazinobenzenesulfonamide hydrochloride (4) in ethanol. All the newly synthesized target compounds (5a-k) were screened for their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compounds 5g and 5j showed pronounced anti-inflammatory activity comparable to the reference standard nimesulide, whereas, compounds 5b, 5d and 5h displayed good anti-inflammatory activity. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity against two Gram-positive bacteria and two Gram-negative bacteria. Four compounds 5c, 5h-5j showed good broad spectrum activity against all the tested Gram-positive and Gram-negative bacterial strains. Compound 5j could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory and antibacterial profile.

[Hydroxy(tosyloxy)iodo]benzene: a useful hypervalent iodine reagent for the synthesis of hetercocyclic compounds

[Hydroxy(tosyloxy)iodo]benzene, a hypervalent iodine reagent finds extensive use in the synthesis of a wide variety of heterocycles. In this review an effort has been made to present the prolific development in recent years in this area

Inhibitors of apoptosis in testicular germ cells: synthesis and biological evaluation of some novel IBTs bearing sulfonamide moiety.

Pifithrin-α, a known p53 inactivator, inhibits p53-dependant mitochondrial cell death induced by toxins or γ-radiation. It has been found that aromatic IBT analogues of PFT-α are more cytoprotective and nonpeptide-based, isatin sulfonamides selectively inhibit caspases 3 and 7, responsible for mitochondrial mediated apoptosis. Therefore, we envisioned the synthesis of novel IBTs 4 and 5 bearing sulfonamide moiety and observed the mitigating effects of these IBTs in rescue of malathion induced apoptosis in testicular germ cells of goat. Two IBTs (4b; R = CH(3), 5b; R(1) = Cl) showed very high survival rate of cells whereas IBT 4f (R = NO(2)) showed some exceptional behaviour by increasing the apoptosis. These IBTs nullify the cytotoxic effect of malathion on mitochondria, following p53-independent pathway.

Potent antiinflammatory 3-thiazole-4(5)-acetic acids of 1,2-benzisothiazole

Abstract A number of 1,2-benzisothiazole derivatives, having 2-thiazolyl-4(5)-acetic acid moiety attached to position-3 of 1,2-benzisothiazole nucleus, were prepared and evaluated as antiinflammatory agents. Some of these were found to possess excellent level of antiinflammatory activity in carrageenin-induced rat paw edema assay.

4-Functionalized 1,3-diarylpyrazoles bearing benzenesulfonamide moiety as selective potent inhibitors of the tumor associated carbonic anhydrase isoforms IX and XII.

A library of 4-functionalized 1,3-diarylpyrazoles (3a-3h, 5a-5g and 6a-6g) was designed, synthesized and evaluated against four human carbonic anhydrase (CA, EC 4.2.1.1) isozymes representing two cytosolic isozymes hCA I and hCA II, and two transmembrane tumor associated ones, hCA IX and hCA XII. All the twenty two tested compounds exhibited excellent CA activity profile against the four CA isozymes when compared to the reference drug acetazolamide. Six of the tested compounds (3a-3b, 3f, 3h, 6a and 6b) displayed low nanomolar affinity (Ki < 5 nM) for hCA IX whereas seven compounds (3a-3b, 3d-3f, 3h and 6f) displayed Ki < 10 nM against hCA XII. In addition, they acted as selective CA inhibitors of isoforms IX and XII over the physiological isoforms I and II.

Synthesis and biological evaluation of some 4-functionalized-pyrazoles as antimicrobial agents

1,3-Diaryl-4-formylpyrazoles 8 bearing benzenesulfonamide moiety at position-1 were synthesized as important intermediates following Vilsmeier-Haack strategy. Aldehyde moiety of 4-formylpyrazole was then converted into carboxylic acid 9, cyano 10 and carbothioamide 11 using established procedures. Out of these 4-functionalized pyrazoles, pyrazole-4-carboxylic acids 9 and carbothioamides 11 were evaluated for their in vitro antibacterial activity against four pathogenic bacterial strains namely, Staphylococcus aureus, Bacillus subtilis (Gram-positive), Escherichia coli, Pseudomonas aeruginosa (Gram-negative), and in vitro antifungal activity against two pathogenic fungal strains namely, Aspergillus niger and Aspergillus flavus. Three tested compounds, 9e, 11b and 11f exhibited moderate antibacterial activity against Gram-positive bacteria and 9g showed moderate antifungal activity against the tested fungi. However, none of the compounds showed any activity against Gram-negative bacteria.

Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids as calcium activated chloride channel inhibitors

Transmembrane protein 16A (TMEM16A) channels are recently discovered membrane proteins that functions as a calcium activated chloride channel (CaCC). CaCCs are major regulators of various physiological processes, such as sensory transduction, epithelial secretion, smooth muscle contraction and oocyte fertilization. Thirty novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids (B01-B30) were synthesized and evaluated for their TMEM16A inhibitory activity by using short circuit current measurements in Fischer rat thyroid (FRT) cells expressing human TMEM16A. IC(50) values were calculated using YFP fluorescence plate reader assay. Final compounds, having free carboxylic group displayed significant inhibition. Eight of the novel compounds B02, B13, B21, B23, B25, B27, B28, B29 exhibit excellent CaCCs inhibition with IC(50) value <6 μM, with compound B25 exhibiting the lowest IC(50) value of 2.8 ± 1.3 μM. None of the tested ester analogs of final benzofuran derivatives displayed TMEM16A/CaCCs inhibition.

Synthesis and Biophysical Properties of C5-Functionalized LNA (Locked Nucleic Acid)

Oligonucleotides modified with conformationally restricted nucleotides such as locked nucleic acid (LNA) monomers are used extensively in molecular biology and medicinal chemistry to modulate gene expression at the RNA level. Major efforts have been devoted to the design of LNA derivatives that induce even higher binding affinity and specificity, greater enzymatic stability, and more desirable pharmacokinetic profiles. Most of this work has focused on modifications of LNA’s oxymethylene bridge. Here, we describe an alternative approach for modulation of the properties of LNA: i.e., through functionalization of LNA nucleobases. Twelve structurally diverse C5-functionalized LNA uridine (U) phosphoramidites were synthesized and incorporated into oligodeoxyribonucleotides (ONs), which were then characterized with respect to thermal denaturation, enzymatic stability, and fluorescence properties. ONs modified with monomers that are conjugated to small alkynes display significantly improved target affinity, binding specificity, and protection against 3′-exonucleases relative to regular LNA. In contrast, ONs modified with monomers that are conjugated to bulky hydrophobic alkynes display lower target affinity yet much greater 3′-exonuclease resistance. ONs modified with C5-fluorophore-functionalized LNA-U monomers enable fluorescent discrimination of targets with single nucleotide polymorphisms (SNPs). In concert, these properties render C5-functionalized LNA as a promising class of building blocks for RNA-targeting applications and nucleic acid diagnostics.

Benzenesulfonamide bearing 1,2,4-triazole scaffolds as potent inhibitors of tumor associated carbonic anhydrase isoforms hCA IX and hCA XII.

Three series of novel heterocyclic compounds (3a-3g, 4a-4g and 5a-5g) containing benzenesulfonamide moiety and incorporating a 1,2,4-triazole ring, have been synthesized and investigated as inhibitors against four isomers of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozymes hCA I and II, compounds of two series (3a-3g and 4a-4g) showed Ki values in the range of 84-868 nM and 5.6-390 nM, respectively whereas compounds of series 5a-5g were found to be poor inhibitors (Ki values exceeding 10,000 nM in some cases). Against hCA IX and XII, all the tested compounds exhibited excellent to moderate inhibitory potential with Ki values in the range of 2.8-431 nM and 1.3-63 nM, respectively. Compounds 3d, 3f and 4f exhibited excellent inhibitory potential against all of the four isozymes hCA I, II, IX and XII, even better than the standard drug acetazolamide (AZA) whereas compound of the series 5a-5g were comparatively less potent but more selective towards hCA IX and XII.

Efficient RNA-targeting by the introduction of aromatic stacking in the duplex major groove via 5-(1-phenyl-1,2,3-triazol-4-yl)-2'-deoxyuridines

Three pyrimidine nucleosides with differently substituted phenyltriazoles attached to the 5-position were prepared by Cu(I)-assisted azide-alkyne cycloadditions (CuAAC) and incorporated into oligonucleotides. Efficient π-π-stacking between two or more phenyltriazoles in the major groove was found to increase the thermal stability of a DNA:RNA duplex significantly. The best stacking, and most stable duplex, was obtained by a sulfonamide substituted derivative.