Abad Ali

Review: biologically active pyrazole derivatives

Nitrogen-containing heterocyclic compounds and their derivatives have historically been invaluable as a source of therapeutic agents. Pyrazole, which has two nitrogen atoms and aromatic character, provides diverse functionality and stereochemical complexity in a five-membered ring structure. In the past decade, studies have reported a growing body of data on different pyrazole derivatives and their innumerable physiological and pharmacological activities. In part, such studies attempted to reveal the wide range of drug-like properties of pyrazole derivatives along with their structure–activity relationships in order to create opportunities to harness the full potentials of these compounds. Here, we summarize strategies to synthesize pyrazole derivatives and demonstrate that this class of compounds can be targeted for the discovery of new drugs and can be readily prepared owing to recent advances in synthetic medicinal chemistry.

Neurodegenerative diseases linked to misfolded proteins and their therapeutic approaches: A review.

Neurodegenerative diseases, such as Alzheimers, Parkinsons, Creutzfeldt-Jacob, Huntingtons diseases and amyotrophic lateral sclerosis, are mainly characterized by the massive deposition of misfolded protein aggregates consequent to aberrant production or overexpression of specific proteins. The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this review we examine recent progress in the area of neurodegenerative drug discovery, focusing on some of the most common targets.

DFT/B3LYP calculations, in vitro cytotoxicity and antioxidant activities of steroidal pyrimidines and their interaction with HSA using molecular docking and multispectroscopic techniques

As a part of our continuing program on the synthesis of steroidal heterocycles, it has been prepared a series of novel steroidal pyrimidine derivatives 4-6via TMSCl, steroidal ketones (1c-3c), urea and benzaldehyde. The systems presented here, are novel scaffolds and have not been described before at 6th position of steroidal-6-one (1c-3c). Structural assignment of newly synthesized compounds was performed by DFT/B3LYP calculations as well as spectral and analytical data. The interactions of compounds (4-6) with HSA were studied by fluorescence spectroscopy, DLS, CD and molecular docking, under imitated physiological conditions. The antitumor activity has been tested in vitro against three cancer cell lines MDA-MB231 (breast carcinoma), HeLa (human cervical carcinoma), HepG2 (hepatic carcinoma) and one non-cancer normal cell lines, PBMCs (peripheral blood mononuclear cell) by MTT assay. In addition, in vitro antioxidant activity and apoptosis assay of the synthesized compounds (4-6) have also been investigated.

Synthesis and characterization of steroidal heterocyclic compounds, DNA condensation and molecular docking studies and their in vitro anticancer and acetylcholinesterase inhibition activities

A facile, convenient and efficient approach for the synthesis of a new series of steroidal heterocyclic compounds (4–12) by reacting a mixture of compounds (1e–3e) with o-aminothiophenol/o-aminophenol/o-phenylenediamine is reported. The structural assignment of products is confirmed on the basis of IR, 1H NMR, 13C NMR, MS and analytical data. The compounds obey the Lipinskis ‘Rule of Five’ analysis based on computational prediction and pharmacokinetic properties. The anticancer activity has been tested in vitro against three cancer cell lines Hep3B (human hepatocellular carcinoma), MCF7 (human breast adenocarcinoma), HeLa (human cervical carcinoma) and one non-cancer normal cell i.e. PBMCs (peripheral blood mononuclear cell) by MTT assay. In addition, the synthesized compounds are also tested for their in vitro antioxidant activity by various reported methods in which compounds 10–12 exhibited good antioxidant activity. Nonenzymatic degradation of DNA has been investigated. The acetylcholinesterase (AChE) inhibitor activities of the steroidal derivatives are also evaluated using Ellmans method. Moreover, the application of compound 6 as a DNA gene transporter is evaluated by DNA condensation and ascertained by employing TEM and AFM, which illustrate that the compound 6 induces the condensation of CT-DNA. Molecular docking studies further characterize the interaction of the synthesized compounds with DNA.

Molecular spectroscopic and thermodynamic studies on the interaction of anti-platelet drug ticlopidine with calf thymus DNA

Ticlopidine is an anti-platelet drug which belongs to the thienopyridine structural family and exerts its effect by functioning as an ADP receptor inhibitor. Ticlopidine inhibits the expression of TarO gene in S. aureus and may provide protection against MRSA. Groove binding agents are known to disrupt the transcription factor DNA complex and consequently inhibit gene expression. Understanding the mechanism of interaction of ticlopidine with DNA can prove useful in the development of a rational drug designing system. At present, there is no such study on the interaction of anti-platelet drugs with nucleic acids. A series of biophysical experiments were performed to ascertain the binding mode between ticlopidine and calf thymus DNA. UV-visible and fluorescence spectroscopic experiments confirmed the formation of a complex between ticlopidine and calf thymus DNA. Moreover, the values of binding constant were found to be in the range of 103M-1, which is indicative of groove binding between ticlopidine and calf thymus DNA. These results were further confirmed by studying the effect of denaturation on double stranded DNA, iodide quenching, viscometric studies, thermal melting profile as well as CD spectral analysis. The thermodynamic profile of the interaction was also determined using isothermal titration calorimetric studies. The reaction was found to be endothermic and the parameters obtained were found to be consistent with those of known groove binders. In silico molecular docking studies further corroborated well with the experimental results.

Microwave-assisted one pot synthesis, characterization, biological evaluation and molecular docking studies of steroidal thiazoles

In the present manuscript, a series of steroidal thiazole derivatives (4-6, 8) have been synthesized in efficient manner by one step reaction methodology employing microwave irradiation. The synthesis involves the reaction of steroidal ketones (1-3, 7) with thiosemicarbazide and phenacyl bromide. Structural assignment of the products was confirmed on the basis of IR, 1H NMR, 13C NMR, MS and analytical data. The synthesized compounds were screened for in vitro antioxidant activity by using 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. In addition, the products 4-6, 8 were also tested for pBR322 DNA cleavage activity, genotoxicity, reactive oxygen species (ROS) production and RBC hemolysis. Molecular docking analysis was carried out to validate the specific binding mode of the newly synthesized compounds into the active site of DNA. Docking showed formation of more stable complexes of compounds 4 and 8 with the free binding energies -8.1 and -8kcal/mol, respectively. Hence, it could be suggested that the steroidal compounds bearing a core thiazole scaffold would be a potent biological agent.

Synthesis, crystal structure, Hirshfeld surfaces, and thermal, mechanical and dielectrical properties of cholest-5-ene

Abstract The title compound derived from 3β-chlorocholest-5-ene has been synthesized and characterized successfully. A single crystal X-ray investigation of the compound revealed that the van der Waals interactions play a key role in the formation of the elementary structure. Hirshfeld surface analysis was used to visualize the fidelity of the crystal structure. This method permitted the identification of individual types of intermolecular contacts and their impact on crystal packing. Molecules are linked by a combination of C–H⋯H and C⋯H contacts, which have clear signatures in the fingerprint plots. The absorption spectrum exhibited a strong absorption band of approximately 246 nm, and the fluorescence spectrum of the compound showed one broad peak at 367 nm. Thermal studies established that the compound undergoes no phase transition and is stable up to 200 °C. The hardness of the grown crystal increases as the load increases. The electric permittivity of cholest-5-ene decreases with increasing frequency and becomes almost constant at high frequencies.

Aloe emodin, an anthroquinone from Aloe vera acts as an anti aggregatory agent to the thermally aggregated hemoglobin

Aggregation of proteins is a physiological process which contributes to the pathophysiology of several maladies including diabetes mellitus, Huntingtons and Alzheimers disease. In this study we have reported that aloe emodin (AE), an anthroquinone, which is one of the active components of the Aloe vera plant, acts as an inhibitor of hemoglobin (Hb) aggregation. Hb was thermally aggregated at 60°C for four days as evident by increased thioflavin T and ANS fluorescence, shifted congo red absorbance, appearance of β sheet structure, increase in turbidity and presence of oligomeric aggregates. Increasing concentration of AE partially reverses the aggregation of the model heme protein (hemoglobin). The maximum effect of AE was observed at 100μM followed by saturation at 125μM. The results were confirmed by UV-visible spectrometry, intrinsic fluorescence, ThT, ANS, congo red assay as well as transmission electron microscopy (TEM). These results were also supported by fourier transform infrared spectroscopy (FTIR) and circular dichroism (CD) which shows the disappearance of β sheet structure and appearance of α helices. This study will serve as baseline for translatory research and the development of AE based therapeutics for diseases attributed to protein aggregation.

Silica-supported NiO nanocomposites prepared via a sol–gel technique and their excellent catalytic performance for one-pot multicomponent synthesis of benzodiazepine derivatives under microwave irradiation

Heterogeneous and versatile NiO–SiO2 NCs were synthesized by a sol–gel technique and used as a catalyst for the one-pot multicomponent synthesis of benzodiazepine derivatives (4a–u) from a mixture of o-phenylenediamine, aromatic aldehydes and dimedone under microwave irradiation. Tetraethyl orthosilicate (TEOS) was used as a source of SiO2 for the creation of the NiO–SiO2 NCs. This catalytic protocol has many advantages, such as simple work up, inexpensive precursors, short reaction time, high yield and high surface area. The structure and morphology of the prepared nanocatalyst was characterized by using elemental analysis, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDAX) and Fourier transform infrared (FTIR) spectroscopy. 1H NMR, 13C NMR and MS analyses were performed to confirm the synthesized compounds (4a–u). Moreover, the remarkable catalytic properties of the NiO–SiO2 NCs permit easy separation of the catalyst from the reaction mixture without significant loss of catalytic activity.

Facile one-pot multicomponent synthesis and molecular docking studies of steroidal oxazole/thiazole derivatives with effective antimicrobial, antibiofilm and hemolytic properties

Graphical abstract Figure. No caption available. HighlightsSteroidal oxazole/thiazole derivatives are synthesized via one‐pot multicomponent reaction.Exhibit promising in‐vitro antibacterial and antifungal activity.Active in Staphylococcus aureus biofilm inhibition.Indicate good prospects for biocompatibility. &NA; A series of steroidal oxazole and thiazole derivatives have been synthesized employing thiosemicarbazide/semicarbazide hydrochloride and ethyl 2‐chloroacetoacetate with a simple and facile one‐pot multicomponent reaction pathway. The antimicrobial activity of newly synthesized compounds were evaluated against four bacterial strains namely Gram‐negative (Escherichia coli and Pseudomonas aeruginosa) and Gram‐positive bacteria (Staphylococcus aureus and Listeria monocytogenes) in addition to pathogenic fungi (Candida albicans and Cryptococcus neoformans). Bioactivity assay manifested that most of the compounds exhibited good antimicrobial activity. To provide additional insight into antimicrobial activity, the compounds were also tested for their antibiofilm activity against S. aureus biofilm. Moreover, molecular docking study shows binding of compounds with amino acid residues of DNA gyrase and glucosamine‐6‐phosphate synthase (promising antimicrobial target) through hydrogen bonding interactions. Hemolytic activity have been also investigated to ascertain the effect of compounds over RBC lysis and results indicate good prospects for biocompatibility. The expedient synthesis of steroidal heterocycles, effective antibacterial and antifungal behavior against various clinically relevant human pathogens, promising biocompatibility offer opportunities for further modification and potential applications as therapeutic agents.