Pyrazole Containing Anti-HIV Agents: An Update

Background: Pyrazole scaffolds have gained importance in drug discovery and development for various pharmacological activities like antiviral, antifungal, anticancer, antidepressant, anti-inflammatory, antibacterial, etc. Additionally, the pyrazole moiety has shown potent anti-HIV activity as a core heterocycle or substituted heterocycles derivatives (mono, di, tri, tetra, and fused pyrazole derivatives). To assist the development of further potential anti-HIV agents containing pyrazole nucleus, here we have summarized pyrazole containing anti-HIV compounds that have been reported by researchers all over the world for the last two decades. Objective: The present review concentrates on an assortment of pyrazole containing compounds, particularly for potential therapeutic activity against HIV. Methods: Google Scholar, Pubmed, and SciFinder were searched databases with ‘‘pyrazol’’ keywords. Further, the year of publication and keywords ‘‘Anti-HIV’’ filter was applied to obtain relevant reported literature for anti-HIV agents containing pyrazole as a core or substituted derivatives. Results: This review article has shown the comprehensive compilation of 220 compounds containing pyrazole nucleus and possessing anti-HIV activity by sorting approximately 40 research articles from 2001 to date. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (13), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (31), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (88), 3-cyanophenoxypyrazole derivative (130), and 4-(4-chlorophenyl)-5-(4-methyl-5-((4-nitrophenyl)diazenyl)thiazol-2-yl)-3-phenyl-5,6-dihydro-4H-pyrazolo[4,3-d]isoxazole (178) were the most potent mono-, di-, tri-, tetra-substituted, and fused pyrazole derivatives, respectively, which have shown potent anti-HIV activity among all the described derivatives as compared with standard anti-HIV drugs. Conclusion: This review article provides an overview of the potential therapeutic activity of pyrazole derivatives against HIV that will be helpful for designing pyrazole containing compounds for anti-HIV activity.

Water Mediated One-Pot, Stepwise Green Synthesis, Anti-Inflammatory and Analgesic Activities of (3-Amino-1-Phenyl-1H-Benzo[f]Chromen-2-yl) (1H-Indol-3-yl) Methanone Catalysed by L-Proline

Aim: The reactions were carried out by one pot three-component synthesis, 3-cyanoacetylindole (1) on reaction with aromatic aldehydes (2) and β-naphthol (3) in an aqueous medium in presence of L-proline as a catalyst under reflux for 30 min, resulted (3-amino-1-phenyl-1H-benzo[f]chromen-2-yl) (1H-indol-3-yl)methanone (4). The method has many advantages like short reaction times, good yields and simple workup procedure besides being green in nature. Pharmacological evaluation of title compounds was done for anti-inflammatory and analgesic activities. Anti-inflammatory activity was carried carrageenan-induced paw edema model in which indomethacin was used as standard and analgesic activity was evaluated by eddy's hot plate method using diclofenac as standard drug. Background: Benzopyrans or chromenes are an important class of heterocyclic compounds due to their broad spectrum of biological activity and a wide range of applications in medicinal chemistry. The chromene moiety is found in various natural products with interesting biological properties. Chromenes constitute the basic backbone of various types of polyphenols and are widely found in alkaloids, tocopherols, flavonoids and anthocyanins. Indoles are omnipresent in various bioactive compounds like alkaloids, agrochemicals and pharmaceuticals. Objective: To synthesize one-pot stepwise Green synthesis, anti-inflammatory and analgesic activities of 3-amino-1-phenyl-1H-benzo[f]chromen-2-yl) (1H-indol-3-yl)methanones Methods: The acute anti-inflammatory effect was evaluated by carrageenan-induced mice paw edema (Ma Rachchh et al., 2011). Edema was induced by injecting carrageenan (1% w/v, 0.1 ml) in the right hind paw of mice. The test compounds 1-12, indomethacin (10 mg/kg) and the vehicle were administered orally one hour before injection of carrageenan. Paw volume was measured with digital plethysmometer at 0, 30, 60, 90, 120 min after injection. Percentage increase =A-B/ A *100 Results: Carrageenan Induced paw edema model was used for Anti-inflammatory activity in which animals treated with standard (indomethacin) and test compounds showed a significant decrease in the paw edema. Analgesic activity was estimated by using Eddy’s hot plate method; animals were treated with standard (diclofenac) and test compounds showed a significant increase in the reaction time. Conclusion: A green, One-pot, step-wise and three-component synthesis of 3-amino-1-phenyl-1H-benzo[f]chromen-2-yl) (1H-indol-3-yl) methanone was achieved by using water as a solvent, L-proline as catalyst under reflux conditions. The reactions were carried out in eco-friendly conditions with shorter reaction times, easier workup and high yields. Anti-inflammatory activity was evaluated by carrageenan-induced paw edema model where significant anti-inflammatory activity is shown by all the test compounds (4a-l) when compared to standard drug. Analgesic activity was studied by Eddy’s Hot plate method and Test compounds 4e, 4f, 4h, 4i, 4j, 4k, 4l showed significant activities when compared to the reference drug.

2-Substituted Benzoxazoles as Potent Anti-Inflammatory Agents: Synthesis, Molecular Docking and In Vivo Anti-Ulcerogenic Studies

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonly used therapeutic interventions of inflammation and pain that competitively inhibit the cyclooxygenase (COX) enzymes. Several side effects like gastrointestinal and renal toxicities are associated with the use of these drugs. The therapeutic anti-inflammatory benefits of NSAIDs are produced by the inhibition of COX-2 enzymes, while undesirable side effects arise from the inhibition of COX-1 enzymes. Objectives: In the present study, a new series of 2-substituted benzoxazole derivatives 2(a-f) and 3(a-e) were synthesized in our lab as potent anti-inflammatory agents with outstanding gastro-protective potential. The new analogs 2(a-f) and 3(a-e) were designed depending upon the literature review to serve as ligands for the development of selective COX-2 inhibitors. Methods: The synthesized analogs were characterized using different spectroscopic techniques (FTIR, 1HNMR, 13CNMR) and elemental analysis. All synthesized compounds were screened for their binding potential in the protein pocket of COX-2 and evaluated for their anti-inflammatory potential in animals using the carrageenan-induced paw edema method. Further 5 compounds were selected to assess the in vivo anti-ulcerogenic activity in an ethanol-induced anti-ulcer rat model. Results: Five compounds (2a, 2b, 3a, 3b and 3c) exhibited potent anti-inflammatory activity and significant binding potential in the COX-2 protein pocket. Similarly, these five compounds demonstrated a significant gastro-protective effect (p<0.01) in comparison to the standard drug, Omeprazole. Conclusion: Depending upon our results, we hypothesize that 2-substituted benzoxazole derivatives have excellent potential to serve as candidates for the development of selective anti-inflammatory agents (COX-2 inhibitors). However, further assessments are required to delineate their underlying mechanisms.

Synthesis and Evaluation of bis-Schiff Bases of Carbohydrazide as Antioxidant and Cytotoxic Agents

Background & Introduction : Antioxidants are known to prevent oxidative stress-induced damage to the biomolecules and thus, delay the onset of cancers and many age-related diseases. Therefore, the development of novel and potent antioxidants is justified. Method: During this study, we synthesized symmetrical bis-Schiff bases of carbohydrazide 1-27, and evaluated their in vitro antioxidative activity and cytotoxic activity. Results: Among synthesized compounds, six compounds 20 (IC50 = 12.89 ± 0.02 µM), 16 (IC50 = 14.32 ± 0.43 µM), 17 (IC50 = 18.52 ± 0.83 µM), 19 (IC50 = 22.84 ± 0.62 µM), 24 (IC50 = 35.1 ± 0.82 µM) and 15 (IC50 = 40.03 ± 1.06 µM) showed an excellent 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, better than the standard butylatedhydroxyanisole (BHA) (IC50 = 44.6 ± 0.6 µM). Likewise, two compounds 16 (IC50 = 4.3 ± 1.3 µM) and 20 (IC50 = 6.6 ± 1.6 µM) showed oxidative burst scavenging activity better than the standard drug ibuprofen (IC50 = 11.2 ± 1.9 µM). Some synthesized compounds showed good to moderate toxicity against prostate cancer (PC-3) cell lines. Conclusion: This study has identified potent antioxidants and good cytotoxic agents with the potential to further investigate.

Mannich Bases: Centrality in Cytotoxic Drug Design

: Mannich bases identified by Professor Carl Mannich have been the most extensively explored scaffolds for more than 100 years now. The versatile biological roles that they play have promoted their applications in many clinical conditions. The present review highlights the application of Mannich bases as cytotoxic agents, categorizing them into synthetic, semisynthetic and prodrugs classes and gives an exhaustive account of the work reported in the last two decades. The methods of synthesis of these cytotoxic agents, their anti-cancer potential in various cell lines and promising leads for future drug development have also been discussed. Structure-activity relationships along with the targets on which these cytotoxic Mannich bases act have been included as well.

Design, Synthesis and Biological Evaluation of Coumarin Derivatives as NEDD8 Activating Enzyme Inhibitors in Pancreatic Cancer Cells

Background: NEDD8 (neural precursor cell expressed developmentally downregulated protein 8) is one of the ubiquitin-like proteins which is activated by the NEDD8 activating enzyme (NAE). The overexpressed NAE can cause a variety of diseases such as numerous cancer types and inflammatory diseases. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment. Objective: In this article, we decided to study the synthesis and screening of coumarin scaffold derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3. Methods: Twenty-four targeted compounds were synthesized, and their anti-proliferative activity against three cancer cell lines, cytotoxicity against three normal cell lines through CCK-8 and MTT assay were evaluated to screen out the candidate compound. Then the target was further confirmed by both enzyme and cell-based experiments, as well as cell apoptosis research. Results: Several new 4-position substituted coumarin derivatives (12a~x) were synthesized and most of them exhibit antiproliferative activity in three cancer cell lines. A series of experiments were performed to identify the best candidate compound 12v. This compound displayed the highest potency against BxPC-3 with an IC50 value of 0.28 µM. It can also inhibit NAE activity in enzyme and cellbased assay, and induce CRLs-mediated accumulation of the substrate and apoptosis in BxPC-3 cells. Meanwhile, it exhibited relatively low toxicity in three normal cells. Conclusion: Based on these results, we found that compound 12v inhibited NAE activity in enzyme and cell-based systems and induced apoptosis in BxPC-3 cells. Additionally, it also had a low toxicity. These results suggested that 12v may be promising lead compounds for the development of new anticancer drugs.

Current Research on Pro-Drug Therapies for Parkinson's and Alzheimer's Disease

: Background: alzheimer's disease (ad) and parkinson's (pd) disease are common neurodegenerative conditions of the central nervous system (cns). Thus, these diseases have only been treated symptomatically since no approved drug is available that provides a complete cure. Objectives: through reading relevant literature published at home and abroad, the method and significance of prodrug strategy to increase the efficacy of ad and pd drugs were discussed. Methods: the biological mechanisms and currently approved drugs for both diseases have been discussed, revealing that most of these treatments utilized existing prodrug design strategies, including increased lipophilicity, and the use of transporters mediation and bio-oxidation to improve oral bioavailability and brain permeability. Results: the purpose of this paper is to review the research progress in the treatment of neurodegenerative diseases (ndds), especially ad and pd, using the prodrug strategy. The research of drug bioavailability and the prodrug strategy of cns targeted drug delivery lay the foundation for drug development to treat these diseases. Conclusion: the use of prodrug strategies provides important opportunities for the development of novel therapies for ad and pd.

GreenMolBD: Nature Derived Bioactive Molecules' Database

Aims: One of the most important resources for the development of new drugs is a biologically active lead compound from natural sources. Biomedical researchers and pharmaceutical companies have a high interest in plant-derived molecules that can be used for drug development. Background: The collective knowledge of plants and their phytoconstituents would be of great benefit for the researchers involved in drug design. Therefore, we developed a unique and dynamic database GreenMolBD, to provide collective information of medicinal plants such as their individual profile, chemical constituents and pharmacological evidence, along with their plant parts and extract types based on different studies. Objective: We have also provided a complete profile of each compound, their physical, quantum, drug-likeliness, and toxicity properties (48 type’s descriptor) using in silico tools. Method: 1846 associated targets, related to individual compounds that are already explored in different studies, are also incorporated and synchronized. Result: GreenMolBD is freely accessible and searchable by keywords, plant name, synonym, common name, family name, family synonym, compound name, synonym, IUPAC name, InChI Key, target name and disease name. Conclusion: This is the first evidence-based database of bioactive molecules from medicinal plants specially grown in Bangladesh, which may help to explore and foster nature-inspired rational drug discovery in the future. Our database is continuously updating with the new information.