Sidra Hassan

Isonicotinohydrazones as Inhibitors of Alkaline Phosphatase and Ecto-5'-nucleotidase.

A series of isonicotinohydrazide derivatives was synthesized and tested against recombinant human and rat ecto‐5′‐nucleotidases (h‐e5′NT and r‐e5′NT) and alkaline phosphatase isozymes including both bovine tissue‐non‐specific alkaline phosphatase (b‐TNAP) and tissue‐specific calf intestinal alkaline phosphatase (c‐IAP). These enzymes are implicated in vascular calcifications, hypophosphatasia, solid tumors, and cancers, such as colon, lung, breast, pancreas, and ovary. All tested compounds were active against both enzymes. The most potent inhibitor of h‐e5′NT was derivative (E)‐N′‐(1‐(3‐(4‐fluorophenyl)‐5‐phenyl‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)ethylidene)isonicotinohydrazide (3j), whereas derivative (E)‐N′‐(4‐hydroxy‐3‐methoxybenzylidene)isonicotinohydrazide (3g) exhibited significant inhibitory activity against r‐e5′NT. In addition, the derivative (E)‐N′‐(4′‐chlorobenzylidene)isonicotinohydrazide (3a) was most potent inhibitor against calf intestinal alkaline phosphatase and the derivative (E)‐N′‐(4‐hydroxy‐3‐methoxybenzylidene)isonicotinohydrazide (3g) was found to be most potent inhibitor of bovine tissue‐non‐specific alkaline phosphatase. Furthermore, putative binding modes of potent compounds against e5′NT (human and rat e5′NT) and AP (including b‐TNAP and c‐IAP) were determined computationally.

3-(5-(Benzylideneamino)thiazol-3-yl)-2H-chromen-2-ones: a new class of alkaline phosphatase and ecto-5′-nucleotidase inhibitors

A new series of 3-(2-(benzylideneamino)thiazol-4-yl)-2H-chromen-2-ones has been synthesized. The structures of the compounds were established by means of 1H and 13C NMR spectroscopy. All compounds were evaluated for their potential to inhibit human recombinant ecto-nucleotidases, including human tissue-nonspecific alkaline phosphatase (h-TNAP), tissue specific human intestinal alkaline phosphatase (h-IAP), human and rat ecto-5′-nucleotidase (h-e5′NT & r-e5′NT). All the compounds were found to be potent and selective inhibitors of h-e5′NT, the most active h-e5′NT inhibitors were compounds 7a (IC50 = 0.25 ± 0.07 μM) and 7g (IC50 = 0.28 ± 0.05 μM). Most of the compounds were found to selectively inhibit h-TNAP over h-IAP, with inhibitory activities in the lower micromolar range. The most active h-TNAP inhibition was exhibited by compounds 7h and 7c (IC50 = 0.21 ± 0.04 μM and 0.22 ± 0.03, respectively), which is ≈91 times greater than the inhibitory activity of the standard inhibitor levamisole. Compound 7i was found to be the most potent h-IAP inhibitor (IC50 = 0.05 ± 0.001 μM), exhibiting ≈11 times greater selectivity for h-IAP over h-TNAP. Homology modeling, molecular docking and dynamics studies were carried out to determine the most plausible binding site interactions of potent inhibitors with ecto-nucleotidases.

Synthesis, characterization and biological evaluation of N-(2,3-dimethyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazol-4-yl)benzamides

We report the synthesis of a series of different substituted N-(2,3-dimethyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazol-4-yl)benzamides by making use of a non-steroidal anti-inflammatory drug known as 4-aminophenazone also called as antipyrine, a compound of great interest in drug chemistry. These compounds possess potential biological applications and were screened against human recombinant alkaline phosphatase including human tissue-nonspecific alkaline phosphatase (h-TNAP), tissue specific human intestinal alkaline phosphatase (h-IAP), human placental alkaline phosphatase (h-PLAP) and human germ cell alkaline phosphatase (h-GCAP). These compounds were also tested for their inhibitory potential against recombinant human and rat ecto-5′-nucleotidases (h-e5-NT & r-e5-NT, respectively). All benzamide derivatives inhibited APs to a lesser degree than e5-NT. The reported compounds are of considerable interest for further applications in the field of medicinal chemistry as these compounds have potential to bind nucleotide protein targets.

4-Aminopyridine based amide derivatives as dual inhibitors of tissue non-specific alkaline phosphatase and ecto-5′-nucleotidase with potential anticancer activity

Ecto-nucleotidase members i.e., ecto-5-nucleotidase and alkaline phosphatase, hydrolyze extracellular nucleotides and play an important role in purinergic signaling. Their overexpression are implicated in a variety of pathological states, including immunological diseases, bone mineralization, vascular calcification and cancer, and thus they represent an emerging drug targets. In order to design potent and selective inhibitors, new derivatives of 4-aminopyridine have been synthesized (10a-10m) and their structures were established on the basis of spectral data. The effect of nature and position of substituent was interestingly observed and justified on the basis of their detailed structure activity relationships (SARs) against both families of ecto-nucleotidase. Compound 10a displayed significant inhibition (IC50u202f±u202fSEMu202f=u202f0.25u202f±u202f0.05u202fµM) that was found ≈168 fold more potent as compared to previously reported inhibitor suramin (IC50u202f±u202fSEMu202f=u202f42.1u202f±u202f7.8u202fµM). This compound exhibited 6 times more selectivity towards h-TNAP over h-e5NT. The anticancer potential and mechanism were also established using cell viability assay, flow cytometric analysis and nuclear staining. Molecular docking studies were also carried out to gain insight into the binding interaction of potent compounds within the respective enzyme pockets and herring-sperm DNA.

Synthesis of novel (E)-1-(2-(2-(4(dimethylamino) benzylidene) hydrazinyl)-4-methylthiazol-5-yl)ethanone derivatives as ecto-5′-nucleotidase inhibitors

Ecto-5′-nucleotidase (e5′NT), a membrane-bound enzyme and an essential member of ecto-nucleotidases which regulates extracellular purinergic signalling. Their upregulation results in various disease conditions, for example, inflammation, hypoxia and cancer. Therefore, efforts have been made to synthesize potent and selective inhibitors of e5′NT. Here we have synthesized, characterized and evaluated six thiazole derivatives (3a–3f) as potent e5′NT inhibitors. Among all derivatives, the compound (E)-1-(4-methyl-2-(2-(pyridin-3-ylmethylene)hydrazinyl) thiazol-5-yl)ethanone (3a) exhibited maximum inhibition towards both human and rat enzymes. However, their potency against h-e5′NT was 24-fold higher than r-e5′NT. Only two compounds exhibited inhibitory behaviour towards r-e5′NT. The molecular structures of these derivatives were confirmed with the help of solid-state characterization through NMR (1H and 13C), FTIR and elemental analysis. Additionally, molecular docking was also implemented to explain putative bonding interaction between the active site of an enzyme and potent inhibitors.

CCDC 1848956: Experimental Crystal Structure Determination

Related Article: Rodisnel P. Rivera, Sidra Hassan, Peter Ehlers, Joanna Lecka, Jean Sevigny, Eugenio T. Rodriguez, Jamshed Iqbal, Peter Langer|2018|Chem. Sel.|3|8587|doi:10.1002/slct.201800917

CCDC 1848957: Experimental Crystal Structure Determination

Related Article: Rodisnel P. Rivera, Sidra Hassan, Peter Ehlers, Joanna Lecka, Jean Sevigny, Eugenio T. Rodriguez, Jamshed Iqbal, Peter Langer|2018|Chem. Sel.|3|8587|doi:10.1002/slct.201800917

Ectonucleotidase Inhibitory and Redox Activity of Imidazole‐Based Organic Salts and Ionic Liquids

Cytotoxicity against cancer and normal cells, inhibition of ectonucleotidase, and redox properties of a new group of imidazole‐based organic salts and ionic liquids were studied. The tetrachloroferrate salt of a 1‐methylimidazole derivative of salicylic aldehyde had most prominent inhibitory activity against ectonucleotidase as well as a higher cytotoxicity against HeLa cells and lower cytotoxicity against BHK‐21 cells than the reference compound carboplatin. The studied compounds exhibited a moderate level of antioxidant activity with better results for the salicylic aldehyde derivatives than for spiropyrans. Moreover, these compounds did not generate singlet oxygen.

Phytocosmeceutical formulation development, characterization and its in-vivo investigations

Several plants found rich in flavonoid, polyphenols, and antioxidants reported antiaging, oppose inflammation and carcinogenic properties but have rarely been applied in dermatology. The present study was an active attempt to formulate a stable phytocosmetic emulsion system loaded with 2% pre-concentrated Prosopis cineraria bark extract, aiming to revive facial skin properties. In order to obtain potent therapeutic activities, we first prepared extracts of stem, leaves, and bark and screen them on basis of phenolic, flavonoids contents and antioxidant, antibacterial, lipoxygenase and tyrosinase inhibition activities. Furthermore, cytocompatibility of the extract was also determined prior starting in vivo investigations. Then the in vivo performance of 2% bark extract loaded emulsion formulation was determined by using non-invasive probe cutometer and elastometer with comparison to base formulation. The preliminary experiment showed that bark extract has a significant amount of phenolic and flavonoid compounds with eminent antioxidant potential. Furthermore, indicated an efficient antibacterial, lipoxygenase, and tyrosinase enzyme inhibition activities. Importantly, the bark extract did not induce any toxicity or apoptosis, when incubated with HaCat cells. Moreover, the in vivo results showed the formulation (size 3u2009μm) decreased the skin melanin, erythema and sebum contents up to 2.1-,2.7-and 79%, while increased the skin hydration and elasticity up to 2-folds and 22% as compared to the base, respectively. Owing to enhanced therapeutic effects the phytocosmetic formulation proved to be a potential skin whitening, moisturizer, anti-acne, anti-wrinkle, anti-aging therapy and could actively induce skin rejuvenation and resurfacing.