Syed Jawad Ali Shah

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.

Investigation of quinoline-4-carboxylic acid as a highly potent scaffold for the development of alkaline phosphatase inhibitors: synthesis, SAR analysis and molecular modelling studies

The role played by organic chemistry in the pharmaceutical industry continues to be one of the main drives in the drug discovery process. More than ever, the industry demands from organic chemists the development of small molecules, which could be a rich source of biological potential. In this context, a diverse range of quinoline-4-carboxylic acid derivatives has been synthesized and evaluated as potent inhibitors of alkaline phosphatases. The structural build-up of the synthesized compounds was based on the spectro-analytical data. Most of the tested compounds showed remarkable inhibition of human tissue-nonspecific alkaline phosphatase (h-TNAP), tissue specific human intestinal alkaline phosphatase (h-IAP) and human placental alkaline phosphatase (h-PLAP). Among them, 3j was identified as a potent inhibitor of h-TNAP with an IC50 value of 22 ± 1 nM, whereas, 3e emerged as a lead candidate against h-IAP and h-PLAP with IC50 values of 34 ± 10 and 82 ± 10 nM, respectively. 3a was a potent inhibitor of human germ cell alkaline phosphatase (h-GCAP) with an IC50 value of 150 ± 70 nM. The putative binding sites of the most potent inhibitors were inferred from molecular docking simulations using homology models based on the h-PLAP structure.

Influence of the diversified structural variations at the imine functionality of 4-bromophenylacetic acid derived hydrazones on alkaline phosphatase inhibition: synthesis and molecular modelling studies

Alkaline phosphatase (AP) isozymes are present in a wide range of species from bacteria to humans with an ability to dephosphorylate and transphosphorylate a wide range of substrates. In humans, four AP isozymes have been identified such as tissue-nonspecific (TNAP), intestinal (IAP), placental (PLAP) and germ cell (GCAP) APs. Modulation of the activity of the different AP isozymes may have therapeutic implications in distinct diseases and cellular processes. To identify potent inhibitors of APs, a diverse range of 4-bromophenylacetic acid derived hydrazone derivatives has been synthesized and characterized by spectro-analytical methods and, in the case of 4i and 4q, by single crystal X-ray diffraction analysis. Among the tested series, several compounds were identified as lead candidates showing IC50 values from micro to nanomolar ranges. Compound 4k displayed exceptional activity with an IC50 value of 10 nM against h-IAP. This inhibitory effect is ∼10000-fold more potent than the standard drug L-phenylalanine. Compounds 4p, 4g and 4e were potent inhibitors of TNAP, PLAP and GCAP, respectively. Molecular docking studies of the respective potent inhibitors have been carried out to rationalize the important binding modes of the most active inhibitors.

Identification of novel pyrazole–rhodanine hybrid scaffolds as potent inhibitors of aldose reductase: design, synthesis, biological evaluation and molecular docking analysis

In an effort to develop a new class of potent aldose reductase inhibitors, a series of 1,3-diarylpyrazole assimilated 3-substituted 4-oxo-2-thioxo-1,3-thiazolidines (9a–n) was designed, and synthesized in good to excellent yields by a pharmacophore integration approach. The structures of the newly synthesized pyrazole–rhodanine derivatives were established by readily available spectroscopic methods (FTIR, 1H and 13C NMR) and mass spectrometry. The hybrid compounds were evaluated as aldehyde and aldose reductase inhibitors. The biological screening results identified several compounds as remarkable inhibitors of ALR1 and ALR2. Among them, compounds 9c and 9k showed excellent activity (and complete selectivity) towards the aldose reductase enzyme with IC50 values of 1.22 ± 0.67, and 2.34 ± 0.78 μM, respectively, as compared to the standard drug (sorbinil; IC50 = 3.10 ± 0.20 μM). The molecular docking analysis of the most potent inhibitor 9c was performed in order to identify the putative binding modes inside the active pocket of the enzymes. These newly discovered aldose reductase inhibitors are believed to represent valuable lead structures to further streamline the generation of candidate compounds to target a number of pathological conditions, most strikingly long-term diabetic complications.

Synthesis, functionalization and biological activity of arylated derivatives of (+)-estrone

Various novel arylated estrone derivatives, such as 2-aryl-, 4-aryl- and 2,4-diaryl-estrones, by Suzuki-Miyaura reactions. While the synthesis of 4-arylestrones could be carried out under standard conditions, the synthesis of 2-arylestrones and 2,4-diarylestrones required a thorough optimization of the conditions and it proved to be important to use sterically encumbered biaryl ligands. The best results were obtained by the use of RuPhos. Combination of developed Suzuki coupling reactions with subsequent cyclization reactions afforded more complex hybrid structures, containing dibenzofuran, benzocoumarin and steroid moieties. These derivatives were tested as pancreatic lipase inhibitors and it was found that most of the compounds exhibited inhibition of pancreatic lipase but the maximum inhibitory potential was shown by 4-arylestrones. All of the synthesized derivatives showed inhibitory values in the range of 0.82±0.01-59.7±3.12μM. The biological activity was also rationalized on the bases of docking studies.

Biological Evaluation of Azomethine-dihydroquinazolinone Conjugates as Cancer and Cholinesterase Inhibitors

In an attempt to discover novel anti-cancer agents and potent cholinesterase inhibitors, 11 azomethine-dihydroquinazolinone conjugates were evaluated against lung carcinoma cells and cholinesterases. Most of the compounds exhibited significant cytotoxicity at low micromolar concentrations and were less toxic to normal cells. After 24 h incubation period, 2i showed maximum cytotoxicity. The 4-bromine substituted compounds showed higher acetylcholinesterase (AChE) inhibitory activity than other screened compounds. The most active compound 2c, among the series, had an IC50 value 209.8 µM against AChE. The tested compounds showed less inhibition against butyrylcholinesterase. Molecular docking studies were performed in order to investigate the plausible binding modes of synthesized compounds. The compounds can be further optimized to treat cancer and Alzheimers disease. These derivatives may open new pathways for introducing new therapies for curing cancer and senile dementia.

Syntheses, Cholinesterases Inhibition, and Molecular Docking Studies of Pyrido[2,3‐b]pyrazine Derivatives

Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimers disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3‐b]pyrazines (6a‐6q) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3‐b]pyrazines showed 3‐(3′‐nitrophenyl)pyrido[2,3‐b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC50 values of 0.466 ± 0.121 and 1.89 ± 0.05 μm, respectively. The analogues 3‐(3′‐methylphenyl)pyrido[2,3‐b]pyrazine 6c and 3‐(3′‐fluorophenyl)pyrido[2,3‐b]pyrazine 6f were found to be selective inhibition for BChE with IC50 values of 0.583 ± 0.052 μm and AChE with IC50 value of 0.899 ± 0.10 μm, respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors.

Synthesis of optically pure ( S )-2-amino-5-arylpent-4-ynoic acids by Sonogashira reactions and their potential use as highly selective potent inhibitors of aldose reductase

A new and convenient synthesis of optically pure (S)-2-amino-5-[aryl]pent-4-ynoic acids (alkynylated amino acids) is reported. (S)-2-Aminopent-4-ynoic acid-Ni-(S)-BPB was prepared and then functionalized via Sonogashira cross-coupling reactions to give (S)-2-amino-5-[aryl]pent-4-ynoic acid-Ni-(S)-BPB. The reaction conditions for the cross-coupling reaction were optimized and twelve derivatives were synthesized. Afterwards the Ni-complexes were cleaved to obtain the free (S)-2-amino-5-[aryl]pent-4-ynoic acids with excellent optical purity. The prepared (S)-2-amino-5-[aryl]pent-4-ynoic acids were tested for biological activity and selectively showed high inhibitory activity against aldose reductase (ALR2) over ALR1. Molecular docking studies have also been carried out to identify the putative binding mode of the compounds in these enzymes.

Molecular dynamic simulations reveal structural insights into substrate and inhibitor binding modes and functionality of Ecto-Nucleoside Triphosphate Diphosphohydrolases

Ecto-nucleotidase enzymes catalyze the hydrolysis of extracellular nucleotides to their respective nucleosides. Herein, we place the focus on the elucidation of structural features of the cell surface located ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDase1-3 and 8). The physiological role of these isozymes is crucially important as they control purinergic signaling by modulating the extracellular availability of nucleotides. Since, crystal or NMR structure of the human isozymes are not available – structures have been obtained by homology modeling. Refinement of the homology models with poor stereo-chemical quality is of utmost importance in order to derive reliable structures for subsequent studies. Therefore, the resultant models obtained by homology modelling were refined by running molecular dynamic simulation. Binding mode analysis of standard substrates and of competitive inhibitor was conducted to highlight important regions of the active site involved in hydrolysis of the substrates and possible mechanism of inhibition.

Synthesis and phosphatase inhibitory activity of 3-alkynylestrones and their derivatives

A range of 3-alkynylated 3-deoxy-estrones were prepared by Sonogashira reactions and transformed into estrone derived diones and quinoxalines. The alkynylated estrones and their derivatives exhibit significant biological activity as alkaline phosphatase inhibitors. The mode of action was illustrated based on docking studies.