Letters in Drug Design & Discovery - Volume 18, Issue 2, 2021

Background: Quinolines are an important class of heterocyclic compounds possessing a wide range of biological activities. Previously, we had identified Schiff bases of quinoline as potential anti-inflammatory agents, thus the current work is the continuation of our previous study. Objective: In the current study, 3-, 5-, and 8-sulfonamide and 8-sulfonate derivatives of quinoline (1-50) were synthesized and their anti-inflammatory potential was evaluated. These synthetic analogs were evaluated for their anti-inflammatory activity via ROS (Reactive oxygen species) inhibitory effect produced from phagocytes from human whole blood. Methods: The sulfonamide and sulfonate derivatives of quinoline were synthesized via treating 5-, 3-, 8-amino, and 8-hydroxy quinolines with different substituted sulfonyl chlorides in pyridine. The synthetic molecules were characterized using various spectroscopic techniques and screened for their anti-inflammatory potential. Results: Among the synthetic derivatives 1-50, six compounds showed good to moderate antiinflammatory activity. Compounds 47 (IC50 = 2.9 ± 0.5 μg/mL), 36 (IC50 = 3.2 ± 0.2 μg/mL), and 24 (IC50 = 6.7 ± 0.3 μg/mL) exhibited enhanced activity as compared to the standard ibuprofen (IC50 = 11.2 ± 1.9 μg/mL). Compounds 20 (IC50 = 25.5 ± 0.7 μg/mL), 50 (IC50 = 42.9 ± 5.6 μg/mL), and 8 (IC50 = 53.9 ± 3.1 μg/mL) were moderately active, however, rest of the compounds were found to be inactive. Conclusion: The sulfonamide and sulfonate derivatives of quinoline were found to have promising anti-inflammatory activity. Further studies on the modification of these molecules may lead to the discovery of new and potential anti-inflammatory agents.

Background: The discovery of novel antidiabetics for the treatment of type 2 diabetes mellitus (T2DM) is an important task nowadays because the current treatment approaches have certain limitations. The reported studies showed that the protein tyrosine phosphatase 1B (PTP1B) is a valuable target, can be used to develop significant antidiabetic molecules. Objective: In the present investigation, computational methods and biological evaluation studies have been applied to develop novel PTP1B inhibitors with good enzyme binding affinity and activity. Methods: Virtual screening (docking) analysis of SPECS database compounds on PTP1B enzyme was performed using Schrodinger software. In vitro and in vivo biological evaluations had been conducted with the identified hits. Results: The results revealed that the molecules identified through these studies have shown significant interactions with the active site residues of the PTP1B enzyme. The compounds S1 and S2 provided significant binding interactions with the residues (Arg221 and Gln262) and have shown considerable in vitro PTP1B inhibitory activity and in vivo antidiabetic activity. The compounds S1 and S2 possessed 35.44±0.12% and 33.68±0.08% inhibitory activities, respectively. Conclusion: These identified hits will be used as a template for design and development of novel PTP1B inhibitors with a compatible pharmacokinetic profile.

Background: The ligand and structure based integrated strategies are being repeatedly and effectively employed for the precise search and design of novel ligands against various disease targets. Aroylindole derivative has a similar structural analogy as Combretastatin A-4, and exhibited potent anticancer activity on several cancer cell lines. Objective: To identify structural features of aroylindole derivatives through 3D-QSAR and multiple pharmacophore modelling for the search of novel colchicines inhibitor via virtual screening. Methods: The present study utilizes ligand and structure based methodology for the establishment of structure activity correlation among trimethoxyaroylindole derivatives and the search of novel colchicines inhibitor via virtual screening. The 3D-QSAR studies were performed using Phase module and provided details of relationship between structure and biological activity. A single ligand based pharmacophore model was generated from Phase on compound 3 and compound 29 and three energetically optimized structure based pharmacophore models were generated from epharmacophore for co-crystallized ligand, compound 3 and compound 29 with protein PBD ID 1SA0, 5EYP and 5LYJ. These pharmacophoric features containing hit-like compounds were collected from commercially available ZINC database and screened using virtual screening workflow. Results and Discussion: The 3D-QSAR model studies with good PLSs statistics for factor four was characterized by the best prediction coefficient Q² (0.8122), regression R² (0.9405), SD (0.2581), F (102.7), P (1.56e-015), RMSE (0.402), Stability (0.5411) and Pearson-r (0.9397). The generated epharmacophores have GH scores over 0.5 and AUAC ≥ 0.7 indicated that all the pharmacophores were suitable for pharmacophore-based virtual screening. The virtual screened compounds ZINC12323179, ZINC01642724, and ZINC14238006 have showed similar structural alignment as co-crystallized ligand and showed the hydrogen bonding of ligand with ASN101, SER178, THR179, VAL238, CYS241 amino acid of protein. Conclusion: The study illustrates that the ligand and structure based pharmacophoric approach is beneficial for identification of structurally diverse hits, having better binding affinity on colchicines binding site as novel anticancer agents.

Background: Diabetes mellitus (DM) is the most severe, chronic metabolic disorder with abnormally elevated concentration of plasma glucose levels, leading to significant complications, such as diabetic neuropathy, retinopathy, and cardiovascular illnesses. Objective: Synthetic drugs have some disadvantages and limitations. Therefore, there is a continuous global and insisting need for new and better treatment options for Diabetes Mellitus. Method: In this study, 42 natural anti-diabetic constituents like alkaloids, glycosides, and flavonoids were selected on the basis of mechanism of action on various molecular targets such as Glucokinase activator, Dipeptidyl peptidase 4 (DPP-4), peroxisome proliferator-activated receptors (PPARγ), and α-glucosidase inhibitor. To investigate the potential molecular targets for natural antidiabetcs agents, molecular docking study was carried out using the Glide module of Schrodinger Suit. Result: Interactions of specific amino acid of the targets with the atoms of the chemical constituents and their Gscore indicate the proper binding of chemical constituents with target. The results revealed that Myricetin, Quercetin ae interacts with active sites of the target chosen and can be used for the designing of novel compounds as anti-dibetics. Conclusion: Calculated GScore could be used as a preliminary tool for screening of anti-diabetic drugs before performing experimental activity.

Background: Pipemidic acid is a broad-spectrum quinolone antibacterial agent for the treatment of chronic urinary tract infections against both gram-positive and gram-negative bacteria. Both quinolone and fluoroquinolone antibiotics have been useful in combating bacterial infections. However, patients suffer severe side effects when they stop taking the medication. The piperazinyl region of pipemidic acid is highly responsible for the side effects. Objective: The objective of this study is to design new compounds in which the piperazinyl region is masked by way of conjugation to benzoic acid derivatives. Methods: In silico studies were conducted using AutoDockTools software for ligand-protein docking. The docking scores were compared to the parent pipemidic acid docked to Bacterial DNA (deoxyribonucleic acid) gyrase and GABA (gamma-Aminobutyric acid) receptor from the PDB (Protein Data Bank) database. Sites of metabolism, biological activity, quantum chemical descriptors, and ADME (absorption, distribution, metabolism, and excretion) property predictions for each designed ligand were also evaluated. Results: The docking studies and biological activity predictions showed good anti-infective properties (ligand PAR03) whilst also suggesting a reduction in GABA receptor agonist activity. The performance of PAR03 correlates with its electronic properties showing electrophilic character (can generate Reactive Electrophilic Species (RES)). Conclusion: The results from this study indicate that modification of the piperazinyl region of pipemidic acid can be an effective way to improve the drug potency whilst also ensuring reduction of the associated side effects.

Background: Oxadiazole fragment is one of the most prevalent structures in biochemicals, especially in the research of new pesticides. It is necessary to develop new insecticides with a different mode of action for the treatment of insecticide resistance problems. And, it is worth exploring the new active insecticidal lead structures with oxadiazole fragments. Methods: We used a “splicing up” method introducing the trifluoromethyl-oxadiazole moiety to 3- (ethylsulfonyl)-pyridine structure, and replaced the 6-position on the pyridine ring by different substituted amines. Then, a series of novel 3-(ethylsulfonyl)-pyridines containing trifluoromethyloxadiazole moiety were designed and synthesized. All these title compounds were confirmed by ¹H NMR, ¹³C NMR and ESI-MS. Results: The primary insecticidal activity results indicated that some of them (A1-A7, A10, A13- A14) exhibited good mortality against Mythimna separate at 500 mg/L (80-100%), and compounds A13 and A14 have moderate insecticidal activity against M. separate at 250 mg/L (50-55%). Discussion: The bioassay results showed that the designed compounds did not achieve excellent insecticidal activity by introducing the potential oxadiazole fragment. Therefore, it seems that the special physicochemical properties of the oxadiazole fragment should be considered in fragment splicing-based design. Conclusion: According to the bioassay studies, the results revealed that compounds A13 and A14 may provide useful information for further designing of efficient insecticides.

Background: Compound containing sulfonamide, pyrazole and chalcone groups are important in medicinal chemistry. They have a wide range of biological activities, including carbonic anhydrase (CA) inhibitory activities. Introduction: Carbonic anhydrase I and II inhibitors are used for the treatment of diseases, such as retinal and cerebral edema (CA I), epilepsy, and glaucoma (CA II). However, the currently available drugs have some limitations or side effects. Thus, there is a need for new drug candidates to overcome these issues. In this study, a series of compounds, (E)-4-(4-(3-aryl)-3-oxoprop-1-en-1-yl)- 3-phenyl-1H-pyrazol-1-yl) benzenesulfonamides MS4-MS10, were designed to discover new CA inhibitors using a hybrid approach. Methods: Compounds MS4-MS10 were synthesized as shown in Scheme 1, and their chemical structures were confirmed by ¹H NMR, ¹³C NMR, and HRMS spectra. The CAs (E.C.4.2.1.1) inhibitory effects of MS4-MS10 were tested on the hCA I and II isoenzymes using previously reported procedures. Results: The CA inhibitors MS4–MS10 gave IC50 values (nM) of 27.8–87.3 towards hCA I and 24.4–54.8 towards hCA II while the IC50 values for reference drug acetazolamide were 384.2 (hCA I) and 36.9 (hCA II). MS7 and MS9 exhibited 13.8 (hCA I) and 1.5 (hCA II) times more potent CA inhibition than the reference compound acetazolamide, respectively. Conclusion: MS7 (Ar: 2,4,5-trimethoxy phenyl) and MS9 (Ar: 3,4-dimethoxy phenyl) were the most promising compounds of our series with the lowest IC50 values towards hCA I and hCA II, respectively, and can be considered for further studies.

Background: Anthraquinone derivatives, frequently occurring motifs in many various natural compounds, have attracted a great deal of interest as compounds with a wide spectrum of biological activities. Introduction: The hybrid pharmacophore approach has become an object of considerable interest due to the incorporation of a five- or six-membered heterocyclic rings in the structure of various natural compounds, especially anthraquinone derivatives. Methods: A series of polyfunctionalized anthraquinonehydrazones have been synthesized via the azo-coupling reaction between anthraquinone-based triazenes and methylene active compounds. The structures of synthesized compounds were confirmed by spectral data. Some of the synthesized compounds were screened for their in vitro anticancer activity according to US NCI protocols. The screening of antimicrobial and antifungal activities against Candida albicans and Lactobacillus sp. was carried out. The synthesized compounds were evaluated for their antioxidant (DPPH free radical scavenging assay) and herbicidal activity. Results: The synthesized 1-[N'-(5-oxo-2-thioxoimidazolidin-4-ylidene)-hydrazino]-anthraquinone 1.5 displayed a high level of antimitotic activity against tested human tumor cells with mean GI50/TGI values 4.06/78.52μM. The screening of antimicrobial and antifungal activities led to the identification of 1.8 and 1.9 with a moderate effect on Candida albicans and Lactobacillus sp. Antioxidant activity evaluation allowed the identification of 1-[N'-(3-methyl-5-oxo-1-phenyl-1,5- dihydropyrazol-4-ylidene)-hydrazino]-anthraquinone 1.8 with an IC50 value of 3.715 mM. The herbicidal activity screening led to compound identification 1.8 with growth inhibition of Agrostis stolonifera at 25 %. Conclusion: The obtained anthraquinonehydrazones constitute an interesting template for the design of new synthetic agents with polypharmacological activities.