Obaid Afzal

A review on anticancer potential of bioactive heterocycle quinoline

The advent of Camptothecin added a new dimension in the field anticancer drug development containing quinoline motif. Quinoline scaffold plays an important role in anticancer drug development as their derivatives have shown excellent results through different mechanism of action such as growth inhibitors by cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. The anti-cancer potential of several of these derivatives have been demonstrated on various cancer cell lines. In this review we have compiled and discussed specifically the anticancer potential of quinoline derivatives, which could provide a low-height flying birds eye view of the quinoline derived compounds to a medicinal chemist for a comprehensive and target oriented information for development of clinically viable anticancer drugs.

Synthesis and pharmacological evaluation of pyrazolo[4,3-c]cinnoline derivatives as potential anti-inflammatory and antibacterial agents.

A series of pyrazolo[4,3-c]cinnoline derivatives was synthesized, characterized and evaluated for anti-inflammatory and antibacterial activity. Test compounds that exhibited good anti-inflammatory activity were further screened for their ulcerogenic and lipid peroxidation activity. Compounds 4d and 4l showed promising anti-inflammatory activity with reduced ulcerogenic and lipid peroxidation activity when compared to naproxen. Docking results of these two compounds with COX-2 (PDB ID: 1CX2) also exhibited a strong binding profile. Among the test derivatives, compound 4i displayed significant antibacterial property against gram-negative (Escherichia coli and Pseudomonas aeruginosa) and gram-positive (Staphylococcus aureus) bacteria. However, compound 4b emerged as the best dual anti-inflammatory-antibacterial agent in the present study.

Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review

Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is approved for the treatment of major depression (including paediatric depression), obsessive-compulsive disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression.

2-Benzamido-4-methylthiazole-5-carboxylic Acid Derivatives as Potential Xanthine Oxidase Inhibitors and Free Radical Scavengers

The new chemical entities febuxostat and topiroxostat have been approved by the US Food and Drug Administration, opening new avenues for exploiting different heterocycles other than purines as xanthine oxidase (XO) inhibitors. A different series of substituted 2‐benzamido‐4‐methylthiazole‐5‐carboxylic acid derivatives (5a–r) was synthesized and characterized by the collective use of IR, 1H and 13C NMR, and mass spectroscopy, for the treatment of gout and hyperuricemia. In vitro studies of the synthesized derivatives revealed that the presence of a fluoro group at the para position in 5b (IC50 = 0.57 μm) and a chloro group in 5c (IC50 = 0.91 μm) signifies excellent XO inhibitory activity among the series, along with their DPPH free radial scavenging activity. In vivo serum uric acid inhibition studies established that 5b and 5c displayed 62 and 53% uric acid inhibition, respectively. Studies on enzyme kinetics indicated that 5b acts as a mixed type inhibitor. In silico prediction by various softwares also helped in the recognition of potent XO inhibitors.

Docking based virtual screening and molecular dynamics study to identify potential monoacylglycerol lipase inhibitors.

Monoacylglycerol lipase (MAGL) is one of the key enzymes of the endocannabinoid system (ECS). It hydrolyzes one of the major endocannabinoid, 2-arachidonoylglycerol (2-AG), an endogenous full agonist at G protein coupled cannabinoid receptors CB1 and CB2. Numerous studies showed that MGL inhibitors are potentially useful for the treatment of pain, inflammation, cancer and CNS disorders. These provocative findings suggested that pharmacological inhibition of MAGL function may confer significant therapeutic benefits. In this study, we presented hybrid ligand and structure-based approaches to obtain a novel set of virtual leads as MAGL inhibitors. The constraints used in this study, were Glide score, binding free energy estimates and ADME properties to screen the ZINC database, containing approximately 21 million compounds. A total of seven virtual hits were obtained, which showed significant binding affinity towards MAGL protein. Ligand, ZINC24092691 was employed in complex form with the protein MAGL, for molecular dynamics simulation study, because of its excellent glide score, binding free energy and ADME properties. The RMSD of ZINC24092691 was observed to stay at 0.1 nm (1 Å) in most of the trajectories, which further confirmed its ability to inhibit the protein MAGL. The hits were then evaluated for their ability to inhibit human MAGL. The compound ZINC24092691 displayed the noteworthy inhibitory activity reducing MAGL activity to 21.15% at 100 nM concentration, with an IC50 value of 10 nM.

ContPro: A web tool for calculating amino acid contact distances in protein from 3D -structures at different distance threshold.

To investigate the functional sites on a protein and the prediction of binding sites (residues)in proteins, it is often required to identify the binding site residues at different distance threshold from protein three dimensional (3D)structures. For the study of a particular protein chain and its interaction with the ligand in complex form, researchers have to parse the output of different available tools or databases for finding binding-site residues. Here we have developed a tool for calculating amino acid contact distances in proteins at different distance threshold from the 3D-structure of the protein. For an input of protein 3D-structure, ContPro can quickly find all binding-site residues in the protein by calculating distances and also allows researchers to select the different distance threshold, protein chain and ligand of interest. Additionally, it can also parse the protein model (in case of multi model protein coordinate file)and the sequence of selected protein chain in Fasta format from the input 3D-structure. The developed tool will be useful for the identification and analysis of binding sites of proteins from 3D-structure at different distance thresholds. Availability It can be accessed at: http://procarb.org/contpro/

Pyrazole incorporated 1,2-diazanaphthalene derivatives: Synthesis and in-vivo pharmacological screening as anti-inflammatory and analgesic agents

In the present study, a new series of compounds (3 to 22) containing pyrazole moiety clubbed with 1,2diazanaphthalene ring, structurally related to celecoxib and naproxen was synthesized. The compounds were evaluated for anti-inflammatory activity using carrageenan induced rat paw edema bioassay. Compounds showing marked anti-inflammatory activity were further tested for their analgesic, ulcerogenic and lipid peroxidation effect using naproxen as reference drug. The results showed that compounds 6, 13 and 14 exhibited good anti-inflammatory and analgesic activity with minimum gastric irritation. Compounds 13 and 14 emerged as potent anti-inflammatory (with percentage inhibition of 79.23 and 76) and analgesic agent (with percentage protection of 68.72 and 67.68) in the present study.

Nꞌ-{(2-(Piperidin-1-yl)quinolin-3-yl)methylene}pyridine-4- carbohydrazide

Nꞌ-{[2-(piperidin-1-yl)quinolin-3-yl]methylene}pyridine-4-carbohydrazide 2 has been synthesized through condensation of 2-(piperidin-1-yl)quinoline-3-carbaldehyde 1 with isonicotinic acid hydrazide (INH) in absolute ethanol. The structure of the title compound 2 was established on the basis of IR, 1H-NMR, 13C-NMR and mass spectral data.

3D-QSAR study of benzotriazol-1-yl carboxamide scaffold as monoacylglycerol lipase inhibitors.

Purpose: The purpose of this study is to build up the 3D pharmacophore of Monoacylglycerol lipase (MAGL) inhibitor and to provide the basis to design the novel and potent MAGL inhibitors. Material and Method: A 3D-QSAR study on benztriazol-1-yl carboxamide derivatives as monoacylglycerol lipase (MAGL) inhibitors was successfully performed by means of pharmacophore mapping using PHASE 3.5 module of Schrφdinger-9.4. Result: The 3D-QSAR obtained from APRRR-105 hypothesis was found to be statistically good with r2 = 0.9228 and q2 = 0.871, taking PLS factor 4. The statistical significance of the model was also confirmed by a high value of Fishers ratio of 82.8 and a very low value of root-mean-square error (RMSE) 0.2564. Another parameter which signifies the model predictivity is Pearson R. Its value of 0.9512 showed that the correlation between predicted and observed activities for the test set compounds is excellent. Conclusion: The study suggested that one H-bond acceptor, one positive center, and proper positioning of hydrophobic groups near the distal aromatic ring C are the crucial determinants for MAGL inhibition. Thus, it can be assumed that the present QSAR analysis is enough to demonstrate MAGL inhibition with the help of APRRR-105 hypothesis and will be helpful in designing novel and potent MAGL inhibitors.

1-(8-Chloro-3-methyl-1H-pyrazolo[4,3-c]cinnolin-1-yl)-2-(2-chlorophenyl)ethanone

1-(8-Chloro-3-methyl-1H-pyrazolo[4,3-c]cinnolin-1-yl)-2-(2-chlorophenyl)ethanone 2 has been synthesized through condensation of 3-acetyl-6-chloro-1H-cinnolin-4-one 1 with 2-(2-chlorophenyl)acetohydrazide in polar aprotic solvent containing catalytic amount of conc. HCl. The structure of the title compound 2 was established on the basis of IR, 1H-NMR, 13C-NMR and mass spectral data.