Mariya al-Rashida

Therapeutic potentials of ecto-nucleoside triphosphate diphosphohydrolase, ecto-nucleotide pyrophosphatase/phosphodiesterase, ecto-5'-nucleotidase, and alkaline phosphatase inhibitors.

The modulatory role of extracellular nucleotides and adenosine in relevance to purinergic cell signaling mechanisms has long been known and is an object of much research worldwide. These extracellular nucleotides are released by a variety of cell types either innately or as a response to patho‐physiological stress or injury. A variety of surface‐located ecto‐nucleotidases (of four major types; nucleoside triphosphate diphosphohydrolases or NTPDases, nucleotide pyrophosphatase/phosphodiesterases or NPPs, alkaline phosphatases APs or ALPs, and ecto‐5′‐nucleotidase or e5NT) are responsible for meticulously controlling the availability of these important signaling molecules (at their respective receptors) in extracellular environment and are therefore crucial for maintaining the integrity of normal cell functioning. Overexpression of many of these ubiquitous ecto‐enzymes has been implicated in a variety of disorders including cell adhesion, activation, proliferation, apoptosis, and degenerative neurological and immunological responses. Selective inhibition of these ecto‐enzymes is an area that is currently being explored with great interest and hopes remain high that development of selective ecto‐nucleotidase inhibitors will prove to have many beneficial therapeutic implications. The aim of this review is to emphasize and focus on recent developments made in the field of inhibitors of ecto‐nucleotidases and to highlight their structure activity relationships wherever possible. Most recent and significant advances in field of NTPDase, NPP, AP, and e5NT inhibitors is being discussed in detail in anticipation of providing prolific leads and relevant background for research groups interested in synthesis of selective ecto‐nucleotidase inhibitors.

Chromone containing sulfonamides as potent carbonic anhydrase inhibitors.

A series of sulfonamide derivatives incorporating substituted 3-formylchromone moieties were investigated for the inhibition of three human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, and VI. All these compounds, together with the clinically used sulfonamide acetazolamide, were investigated as inhibitors of the physiologically relevant isozymes I, II (cytosolic), and VI (secreted isoform). These sulfonamides showed effective inhibition against all these isoforms with KI’s in the range of 0.228 to 118 µM. Such molecules can be used as leads for discovery of novel effective CA inhibitors against other isoforms with medicinal chemistry applications.

Discovery of new chromone containing sulfonamides as potent inhibitors of bovine cytosolic carbonic anhydrase

Series of chromone containing sulfonamides were prepared by the reaction of (un)substituted 3-formylchromones with 3-aminobenzenesulfonamide and 4-aminobenzenesulfonamide. Bovine carbonic anhydrase (bCA) inhibitory activity of these newly synthesized compounds was determined. All compounds were active and possessed excellent bCA inhibitory activities with IC₅₀ values ranged between 4.31 ± 0.001 and 29.12 ± 0.008 μmol. Compounds derived from 6-fluoro-3-formylchromones were the most active.

Schiff bases in medicinal chemistry: a patent review (2010-2015)

ABSTRACT Introduction: Schiff bases are synthetically accessible and structurally diverse compounds, typically obtained by facile condensation between an aldehyde, or a ketone with primary amines. Schiff bases contain an azomethine (-C = N-) linkage that stitches together two or more biologically active aromatic/heterocyclic scaffolds to form various molecular hybrids with interesting biological properties. Schiff bases are versatile metal complexing agents and have been known to coordinate all metals to form stable metal complexes with vast therapeutic applications. Areas covered: This review aims to provide a comprehensive overview of the various patented therapeutic applications of Schiff bases and their metal complexes from 2010 to 2015. Expert opinion: Schiff bases are a popular class of compounds with interesting biological properties. Schiff bases are also versatile metal complexing ligands and have been used to coordinate almost all d-block metals as well as lanthanides. Therapeutically, Schiff bases and their metal complexes have been reported to exhibit a wide range of biological activities such as antibacterial including antimycobacterial, antifungal, antiviral, antimalarial, antiinflammatory, antioxidant, pesticidal, cytotoxic, enzyme inhibitory, and anticancer including DNA damage.

Diarylsulfonamides and their bioisosteres as dual inhibitors of alkaline phosphatase and carbonic anhydrase: Structure activity relationship and molecular modelling studies.

The effect of bioisosteric replacement of carboxamide linking group with sulfonamide linking group, on alkaline phosphatase (AP) and carbonic anhydrase (CA) inhibition activity of aromatic benzenesulfonamides was investigated. A series of carboxamide linked aromatic benzenesulfonamides 1a-1c, 2a-2d and their sulfonamide linked bioisosteres 3a-3d, 4a-4d was synthesized and evaluated for inhibitory activity against bovine tissue non-specific alkaline phosphatase (TNAP), intestinal alkaline phosphatase (IAP) and bCA II. A significant increase in CA inhibition activity was observed upon bioisosteric replacement of carboxamide linking group with a sulfonamide group. Some of these compounds were identified as highly potent and selective AP inhibitors. Compounds 1b, 2b, 3d, 4d 5b and 5c were found to be selective bTNAP inhibitors, whereas compounds 1a, 1c, 2a, 2c, 2d, 3a, 3c, 4a, 4b, 4c, 5a were found to be selective bIAP inhibitors. For most active AP inhibitor 3b, detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase (TNAP) and non-competitive mode of inhibition against intestinal alkaline phosphatase (IAP). Molecular docking studies were carried out to rationalize important binding site interactions.

In search of new α-glucosidase inhibitors: Imidazolylpyrazole derivatives

Under three different reaction conditions (conventional heating, microwave irradiations and amino acid catalysis), a series of imidazolylpyrazoles (2a-2k) were synthesized in good to excellent yields from a mixture of three precursors: aryl(hetaryl)pyrazole-4-carbaldehydes (1a-1k), benzil and ammonium acetate. α-Glucosidase inhibition assay revealed a new class of highly potent agents wherein each compound displayed significant inhibitory potentials (in terms of percentage inhibition and relative IC50 values) as compared to that of the reference drug (Acarbose). Moreover, molecular modelling of most potent compounds 2h, 2j and 2k also helped in understanding the structure and activity relationship.

Hetarylcoumarins: Synthesis and biological evaluation as potent α-glucosidase inhibitors

In search of better α-glucosidase inhibitors, a series of novel hetarylcoumarins (3a-3j) were designed and synthesized through a facile multicomponent route where p-toluenesulfonic acid (PTSA) was explored as an efficient catalyst. These new scaffolds were further evaluated for their α-glucosidase inhibition potentials. All the derivatives exhibited good to excellent results which were comparable or even better than of standard drug acarbose. Of these compounds, a dihalogenated compound 3f was found to be the most effective one with IC50: 2.53±0.002µM. Molecular docking has predicted the plausible binding interactions of compounds 3f, 3g and 3j with α-glucosidase.

Carbonic anhydrase inhibition by 1-aroyl-3-(4-aminosulfonylphenyl)thioureas.

Abstract A series of 1-aroyl-3-(4-aminosulfonylphenyl)thioureas containing free sulfonamide group has been evaluated for their ability to inhibit bovine carbonic anhydrase II (bCA, EC 4.2.1.1). All compounds in the series were able to inhibit bCA II, the most active inhibitor had IC50 value of 0.26 ± 0.01 µM. Molecular docking studies and detailed structure–activity relationship studies were carried out. The absorption, distribution, metabolism, excretion (ADME) properties, as a predictor of oral absorption, were computationally calculated and compared with the clinically used drug acetazolamide.

Novel quinoxaline based chemosensors with selective dual mode of action: nucleophilic addition and host–guest type complex formation

New quinoxalinium salts 1–5 have been exploited as chemosensors via naked eye, UV-Vis absorption, fluorescence quenching and 1H NMR experiments. New sensors 1–5 showed a dual mode, nucleophilic addition and a host–guest type complex towards anion (F−, AcO− and ascorbate) detection. Small anions (F−/AcO−) showed nucleophilic addition at the C2 position of the quinoxalinium cation, while larger anions (ascorbate), revealed the formation of a host–guest type complex due to the steric hindrance posed by the C3 of the phenyl ring. Nucleophilic addition of small anions (F−/AcO−) leads to the de-aromatization of the quinoxalinium cation. However in the case of the larger anion, ascorbate, the host–guest type complex formation induces changes in the absorption/fluorescence signals of the quinoxalinium moiety. This selective binding has been confirmed on the basis of the 1H NMR spectroscopic technique, whereupon nucleophilic addition of small anions (F−/AcO−) was confirmed by monitoring the characteristic proton NMR signals of Ha and the methylene protons (CH2), which were clearly shifted in the cases of fluoride and acetate ion addition confirming the de-aromatization and nucleophilic addition. Whereas no such peak shifting was observed in the case of ascorbate ion addition confirming the non-covalent addition of ascorbate. Theoretical insight into the selectivity and complexation behavior of the ascorbate ion with the quinoxaline moiety is gained through density functional theory (DFT) calculations. Moreover, the absorption properties of these complexes are modeled theoretically, and compared with the experimental data. In addition, the thermal decomposition of sensors (1 and 2) has been studied by the means of differential scanning calorimetry (DSC), thermogravimetry (TG), and differential thermogravimetry (DTG) to signify their utility at variable temperatures.

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.