Zaheer Ul-Haq

Synthesis, antioxidant activities and urease inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives

New series of 4,5-disubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones (8a-j) and 2,5-disubstituted-1,3,4-thiadiazoles (9a-h) were synthesized by dehydrative cyclization of hydrazinecarbothioamide derivatives (7a-k) by refluxing in 4N aqueous sodium hydroxide and by overnight stirring with polyphosphoric acid, respectively. The structures of the newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR, elemental analysis and mass spectroscopic studies and the synthesized compounds were screened for their antioxidant and urease inhibition activities. N-(2,4-Dimethylphenyl)-5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine (9h) showed excellent antioxidant activity more than the standard drug whereas 4-(2,4-dimethylphenyl)-5-(3-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (8d) and 4-(2,3-dimethylphenyl)-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (8e) exhibited potent urease inhibitory activities.

Synthesis and biological activity of oxadiazole and triazolothiadiazole derivatives as tyrosinase inhibitors

A series of 16 oxadiazole and triazolothiadiazole derivatives were designed, synthesized and evaluated as mushroom tyrosinase inhibitors. Five derivatives were found to display high inhibition on the tyrosinase activity ranging from 0.87 to 1.49 microM. Compound 5 exhibited highest tyrosinase inhibitory activity with an IC(50) value of 0.87+/-0.16 microM. The in silico protein-ligand docking using AUTODOCK 4.1 was successfully performed on compound 5 with significant binding energy value of -5.58 kcal/mol. The docking results also showed that the tyrosinase inhibition might be due to the metal chelating effect by the presence of thione functionality in compounds 1-5. Further studies revealed that the presence of hydrophobic group such as cycloamine derivatives played a major role in the inhibition. Piperazine moiety in compound 5 appeared to be involved in an extensive hydrophobic contact and a 2.9A hydrogen bonding with residue Glu 182 in the active site.

Identification of potent urease inhibitors via ligand- and structure-based virtual screening and in vitro assays

A pharmacophore model was developed based on three structurally diverse urease inhibitors by using the GASP program. This model comprises the positions and tolerance for two acceptor atoms (AA1 and AA2), one donor atom (DA1), and one hydrophobic center (HYP1). This derived phamacophore model was employed to screen an in-house database of organic compounds. Hits obtained were evaluated by molecular docking using GOLD software. On the basis of ligand- and structural-based predictions, an in vitro testing of short-listed compounds was conducted and a novel class of urease inhibitors (2-aminothiophines) was identified. The potent in vitro activity and selectivity of these compounds, along with their non-toxic nature against the plant cells indicated that they can serve as leads for solving urease-associated health and agriculture problems.

In silico and in vitro immunomodulatory studies on compounds of Lindelofia stylosa.

Lindolefia stylosa (Kar. and Kir.) is an important medicinal plant in Central and West Asia. Compounds 1 (ethyl lithospermate), 2 (methyl lithospermate), 3 (lithospermate B), 4 (rosmarinic acid), 5 (methyl rosmarinate), 6 (ethyl rosmarinate), 7 (3‐O‐feruloyl‐6′‐O‐coumaroyl sucrose), 8 (3‐O‐feruloyl‐6′‐O‐caffeoyl sucrose), 9 (3,6′‐O‐diferuloyl sucrose), 10 (3,6′‐O‐diferuloyl‐1‐kestose), 11 (3‐O‐feruloyl‐6′‐O‐coumaroyl‐1‐kestose), 12 (3,6′‐O‐diferuloyl nystose), 13 (3‐O‐Feruloyl‐6′‐O‐coumaroyl nystose), 14 (p‐coumaric acid), 15 (ferulic acid), 16 (naphthalene glycoside (8‐O‐β‐D‐glucopyranoside)), and 17 (4′‐hydroxy‐5‐methoxy‐6,7‐methylenedioxyisoflavone), isolated from this plant, were evaluated for their ability to modulate the immune response. Studies included monitoring the effect on reactive oxygen species (ROS) production, T‐lymphocyte proliferation, and inhibition of four cytokines (IL‐2, TNFα, IL‐1β, and IL‐4). These cytokines play a major role in immune response modulation. Molecular docking studies on selected compounds were also conducted, which predict a potent activity of compounds 5 and 6 and moderate activity of compounds 1 and 2 as inhibitors of IL‐2. Correlation between the predicted binding scores and the experimental results was found to be valid. Compound 5 was identified as the most potent IL‐2 inhibitor in the series.

Structure based virtual screening-driven identification of monastrol as a potent urease inhibitor

Virtual screening uses computer based methods to discover new ligands on the basis of biological structures. Among all virtual screening methods structure based docking has received considerable attention. In an attempt to identify new ligands as urease inhibitors, structure-based virtual screening (SBVS) of an in-house database of 10,000 organic compounds was carried out. The X-ray crystallographic structure of Bacillus pasteurii (BP) in complex with acetohydroxamic acid (PDB Code 4UBP) was used as a protein structure. As a starting point, ~10,000 compounds of our in-house database were analyzed to check redundancy and the compounds found repeated were removed from the database. Finally 6993 compounds were docked into the active site of BP urease using GOLD and MOE-Dock software. A remarkable feature of this study was the identification of monastrol, a well-known KSP inhibitor already in clinical trials, as a novel urease inhibitor. The hits identified were further evaluated by molecular docking and on examination of the affinity predictions, twenty-seven analogs of monastrol were synthesized by a multicomponent Biginelli reaction followed by their in vitro screening as urease inhibitors. Finally twelve compounds were identified as new urease inhibitors. The excellent in vitro activity suggested that these compounds may serve as viable lead compounds for the treatment of urease related problems.

Immunosuppressive Activity of Buxidin and E‐Buxenone from Buxus hyrcana

Buxidin (1) and E‐Buxenone (2), steroidal alkaloids from Buxus hyrcana, are found to possess potent immunosuppressive properties. The activity was tested in vitro on oxidative burst, chemotaxis, T‐cell proliferation, and cytokine production. Both compounds showed a significant immunomodulatory activity with clear suppressive effect on oxidative burst and chemotaxis in a dose‐dependent manner. They also exhibited suppressive effect on the phytohemagglutinin‐stimulated T‐cell proliferation. The immunomodulatory activity was further confirmed by the suppression of IL‐2 and IL‐4 production. Furthermore, molecular docking studies were performed to investigate the binding mode of Buxidin (1) and E‐Buxenone (2) with IL‐2. Despite the structural differences between Buxidin (1) and E‐Buxenone (2), docking results revealed that they adopt a similar binding pattern at the active site of the IL‐2. A good agreement between practical and theoretic results indicates that the current docking study could provide an alternate tool for the structural optimization of recently identified ligand as more potent IL‐2 inhibitors.

CoMFA and CoMSIA 3D-QSAR analysis on hydroxamic acid derivatives as urease inhibitors

Urease (EC 3.5.1.5) serves as a virulence factor in pathogens that are responsible for the development of many diseases in humans and animals. Urease allows soil microorganisms to use urea as a source of nitrogen and aid in the rapid break down of urea-based fertilizers resulting in phytopathiCIT000y. It has been well established that hydroxamic acids are the potent inhibitors of urease activity. The 3D-QSAR studies on thirty five hydroxamic acid derivatives as known urease inhibitors were performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods to determine the factors required for the activity of these compounds. The CoMFA model produced statistically significant results with cross-validated (q2) 0.532 and conventional (r2) correlation coefficients 0.969.The model indicated that the steric field (70.0%) has greater influence on hydroxamic acid inhibitors than the electrostatic field (30.0%). Furthermore, five different fields: steric, electrostatic, hydrophobic, H-bond donor and H-bond acceptor assumed to generate the CoMSIA model, which gave q2 0.665 and r2 0.976.This model showed that steric (43.0%), electrostatic (26.4%) and hydrophobic (20.3%) properties played a major role in urease inhibition. The analysis of CoMFA and CoMSIA contour maps provided insight into the possible modification of the hydroxamic acid derivatives for improved activity.

Ligand-based 3D-QSAR studies of physostigmine analogues as acetylcholinesterase inhibitors.

Natural alkaloid Physostigmine is one of the most potent pseudo‐irreversible inhibitor of Acetylcholinesterase. It was found to accelerate long‐term memory process, but due to its short half life and variable bioavailability, has inconsistent clinical efficacy. 3D‐QSAR studies based on the comparative molecular field analysis and comparative molecular similarity indices analysis were applied to a set of 40 Physostigmine derivatives which are divided into two classes: A and B. The study was conducted to obtain a highly reliable and extensive dynamic QSAR model based on alignment procedure with co‐crystallized Ganstigmine as template. The strategy yielded significant 3D‐QSAR models with the cross‐validated q2 values 0.762 and 0.754 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Resulted models were validated by external set of eight compounds yielding high correlation coefficient r2 values of 0.730 and 0.720 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Furthermore, the analysis of comparative molecular field analysis and comparative molecular similarity indices analysis contour maps within the active site of AChE were conducted in order to understand the interactions between the receptor and the Physostigmine derivatives. This study will facilitate the rational design of more potent Physostigmine compounds which might have better activity and reduce toxicity for the treatment of Alzheimer disease.

Synthesis of pyrimidine-2,4,6-trione derivatives: Anti-oxidant, anti-cancer, α-glucosidase, β-glucuronidase inhibition and their molecular docking studies.

This paper describes a facile protocol, efficient, and environmentally benign for the synthesis a series of barbiturate acid substituted at C5 position 3a-o. The desired compounds subjected in vitro for different set of bioassays including against anti-oxidant (DPPH and super oxide scavenger assays), anti-cancer, α-glucosidase and β-glucuronidase inhibitions. Compound 3m (IC50=22.9±0.5μM) found to be potent α-glucosidase enzyme inhibitors and showed more activity than standard acarbose (IC50=841±1.73μM). Compound 3f (IC50=86.9±4.33μM) found to be moderate β-Glucuronidase enzyme inhibitors and showed activity comparatively less than the standard d-saccharic acid 1,4-lactone (IC50=45.75±2.16μM). Furthermore, in sillico investigation was carried out to investigate bonding mode of barbiturate acid derivatives.

BRAF gene: From human cancers to developmental syndromes

The BRAF gene encodes for a serine/threonine protein kinase that participates in the MAPK/ERK signalling pathway and plays a vital role in cancers and developmental syndromes (RASopathies). The current review discusses the clinical significance of the BRAF gene and other members of RAS/RAF cascade in human cancers and RAS/MAPK syndromes, and focuses the molecular basis and clinical genetics of BRAF to better understand its parallel involvement in both tumourigenesis and RAS/MAPK syndromes—Noonan syndrome, cardio-facio-cutaneous syndrome and LEOPARD syndrome.