Medicinal Chemistry - Volume 16, Issue 4, 2020

Matrine-family alkaloids as tetracycloquinolizindine analogues from Traditional Chinese Medicine Sophora flavescens Ait, Sophora subprostrata and Sophora alopecuroides L possess various pharmacological activities and have aroused great interests over the past decades. Especially, a lot of matrine derivatives have been designed and synthesized and their biological activities investigated, and encouraging results have continuously been achieved in recent several years. These studies are helpful to develop more potent candidates or therapeutic agents and disclose their molecular targets and mechanisms. This paper reviews recent advances in the bioactive modifications of matrine-family alkaloids from derivatization of the C-13, C-14 or C-15 position, opening D ring, fusing D ring and structural simplification.

Nitrogen-containing heterocycles are one of the most common structural motifs in approximately 80% of the marketed drugs. Of these, benzimidazoles analogues are known to elicit a wide spectrum of pharmaceutical activities such as anticancer, antibacterial, antiparasitic, antiviral, antifungal as well as chemosensor effect. Based on the benzimidazole core fused heterocyclic compounds, crescent-shaped bisbenzimidazoles were developed which provided an early breakthrough in the sequence-specific DNA recognition. Over the years, a number of functional variations in the bisbenzimidazole core have led to the emergence of their unique properties and established them as versatile ligands against several classes of pathogens. The present review provides an overview of diverse pharmacological activities of the bisbenzimidazole analogues in the past decade with a brief account of its development through the years.

Background: Approximately, 5-7 million people are infected with T. cruzi in the world, and approximately 10,000 people per year die of complications linked to this disease. Methods: This work describes the construction of a new family of hidrazonoyl substituted derivatives, structurally designed exploring the molecular hybridization between megazol and nitrofurazone. Results and Discussion: The compounds were evaluated for their in vitro activity against bloodstream trypomastigotes of Trypanosoma cruzi, etiological agent of Chagas disease, and for their potential toxicity to mammalian cells. Conclusion: Among these hydrazonoyl derivatives, we identified the derivative (4) that showed trypanocidal activity (IC50/24 h = 15.0 μM) similar to Bz, the standard drug, and low toxicity to mammalian cells, reaching an SI value of 18.7.

Background: Silver nanoparticles synthesized by the bio-green method have been applied to various biomedical applications. These procedures are simple, eco-friendly and serve as an alternative to complex chemical methods for the preparation of nanomaterials. Objective: In the present study, phytosynthesis of silver nanoparticles, to examine their antioxidant potential, toxic effects towards bacterial-, fungal-strains, brine shrimp nauplii and cancer cells was focused. Methods: Methanolic extract of Euphorbia wallichii roots was used for the synthesis of silver nanoparticles. The synthesis was monitored and confirmed by UV-visible spectroscopy, Fourier Transform Infra-Red (FTIR) spectrometric analysis, Field Emission Scanning Electron Microscope (FESEM), Energy Dispersive X-ray (EDX) and X-Ray Powder Diffraction (XRD). Results: The synthesized particles were average 63±8 nm in size. Involvement of phenolic (46.7±2.4 μg GAE/mg) and flavonoid (11.7±1.2 μg QE/mg) compounds as capping agents was also measured. Nanoparticles showed antioxidant properties in terms of free radical scavenging potential (59.63±1.0 %), reducing power (44.52±1.34 μg AAE/mg) and total antioxidant capacity (60.48±2.2 μg AAE/mg). The nanoparticles showed potent cytotoxic effects against brine shrimp nauplii (LD50 66.83 μg/ml), proliferation and cell death of HeLa cells as determined by MTT (LD50 0.3923 μg/ml) and TUNEL assays, respectively. Antimicrobial results revealed that silver nanoparticles were found to be more potent against pathogenic fungal (maximum active against A. fumigatus, MIC 15 μg/disc) and bacterial strains (maximum active against S. aureus, MIC 3.33 μg/disc) than the E. wallichii extract alone. Conclusion: These results support the advantages of using an eco-friendly and cost-effective method for synthesis of nanoparticles with antioxidant, cytotoxic and antimicrobial potential.

Background: A novel series of 2-[(2-{[2-(furan-2-yl) quinolin-4-yl] carbonyl} hydrazinyl) carbonyl] benzoic acid, -4-oxobut-2-enoic acid and -4-oxobutanoic acids were synthesized and screened for in vitro antitubercular activity. Objectives: In the present investigation, we describe the synthesis and biological screening of furan C-2 quinoline coupled diamides for antitubercular activity. Methods: The mycobacterium tuberculai testing was carried out by MABA method and molecular docking studies were done by open-source molecular docking program, Autovina, using Pyrx 0.8 interface. Results: The results revealed that the compounds inhibited the growth of H37Rv strain at concentrations as low as 1.6 to 12 μg/ml. Molecular binding of furan, quinoline and diamide (FQD) derivatives on five targets was good and these compounds fit very well within the binding domain of the target protein. Conclusion: The synthesized FQD derivatives exhibited moderate to good inhibition activity especially compounds 5f, 5b and 8a exhibited very good inhibition activity due to the presence of three different scaffolds, such as INH, phenyl ketobutyric acid and fluoroquinolines. Hybridized molecules might have multiple modes of action / inhibit more than one tubercular target and could pave way for novel drug discovery in the field of tuberculosis.

Background: Serotonin is an important biogenic amine and is implicated in wideranging physiological and physiopathological processes. Pharmacological manipulation of the serotoninergic system is believed to have a great therapeutic potential. Objectives: In order to identify selective ligands for 5-HT1A, 5-HT2A and 5-HT2C receptors two series of 4-substituted piperazine derivatives, bearing indolic or methyl indolic nuclei, were synthesized. Methods: All the compounds, synthesized by standard solution methods, were evaluated for 5- HT1A, 5-HT2A and 5-HT2C receptors. The highest affine and selective compounds have been evaluated also on dopaminergic (D1 and D2) and adrenergic (α1A and α2A) receptors. Results: Several of the newly synthesized molecules showed affinity in the nanomolar range for 5- HT1A, 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, α1A and α2A). Conclusion: Compounds 7f and 10a showed a nanomolar affinity towards 5-HT1A with an in vitro pharmacologic profile compatible with antipsychotic drugs.

Background: In continuation of our work on Mannich reaction on 8-hydroxyquinoline, fifteen different combinations of aromatic aldehydes and aniline were subjected to Mannich reaction from which twelve products (eight Mannich bases, two imines and two intramolecularly cyclized products with benzofuranone skeleton) were obtained. Among them six compounds (1, 2, 6, 8, 9 and 12) are the new compounds. The structures of the compounds were characterized by UV, IR, MS and 1H NMR. Methods: The compounds were tested for the inhibition of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β) at a concentration of 25 μg/mL. The cytokines were produced by THP-1 cells differentiated with PMA for 24hrs and stimulated with LPS for 4 hrs and supernatant were analyzed through ELISA technique. Results and Discussion: Compounds 1-5, 8 and 9 inhibited the production of TNF-α and IL-1β. Compounds 1, 3, and 8 exerted potent inhibitions of TNF-α with 71%, 71%, and 83% inhibition, respectively. Compounds 1 and 8 significantly inhibited the production of IL-1β with 64% and 78% inhibition, respectively. Conclusion: Compounds 1 and 8 significantly inhibited the production of IL-1β with 64% and 78% inhibition, respectively. Notably compound 8 showed the most potent inhibition of these cytokines. Additionally, the effect of compounds on viability of THP-1 cells was also evaluated. Moreover, molecular docking was carried out to study the mechanism of inhibition of TNF-α production.

Introduction: Nitric oxide (NO) is an important mediator in the pathogenesis and control of immune system-related disorders and its levels are modulated by inducible NO synthase (iNOS). Oxidative stress is another pathological indication in majority of autoimmune disorders. The present study aims at the development of coupled molecules via selection of pharmacophores for both immunomodulatory and antioxidant activities through iNOS inhibition. Methods: Variedly substituted coumarin moieties are coupled with naturally occurring phenols through an amide linkage and were predicted for activities using computer-based program PASS. The compounds predicted to have dual activities were synthesized. Docking studies were carried out against iNOS (PDB 1R35) and compounds having good docking score were evaluated for immunomodulatory and antioxidant activities. Results: The synthesized compounds were found to be pure and were obtained in good yields. Compounds with maximum docking score (YR1a, YR2e, YR2c and YR4e) were selected for evaluation by in vitro models. Compounds YR2e and YR2c markedly inhibited the reduction of NBT dye and showed maximum % iNOS inhibition. In DPPH assay, compound YR4e was observed as the most potent antioxidant (EC50 0.33 μM/mL). Based on these studies, compounds YR2e and YR2c were selected for haemagglutination test. Compound YR2e was observed as the most active immunosuppressant with maximal inhibitory ability of iNOS and NBT reduction and lower HAT value of 3.5. Conclusion: Compound YR2e can be utilized as a pharmacological agent in the prevention or treatment of immunomodulatory diseases such as tumors, rheumatoid arthritis, ulcerative colitis, organ transplant and other autoimmune disorders.

Background: Histone deacetylases inhibitors (HDACIs) with different chemical structures have been reported to play an important role in the treatment of cancer. Objective: The study aims to modify the structure of Entinostat (MS-275) to discover new compounds with improved anti-proliferative activities and perform SAR studies on this class of bioactive compounds. Methods: Fourteen N-substituted benzamide derivatives were synthesized and their antiproliferative activities were tested with four cancer cell lines (MCF-7, A549, K562 and MDA-MB- 231) by MTT assay. Results: Compared with MS-275, six compounds exhibited comparable or even better antiproliferative activities against specific/certain cancer cell lines. Conclusion: The preliminary SARs showed that (i) the 2-substituent of the phenyl ring in the R group and heteroatoms of amide which can chelate with zinc ion are critical to the antiproliferative activity and (ii) chlorine atom or nitro-group on the same benzene ring largely decreases their anti-proliferative activity. Molecular docking study illustrated the interaction (binding affinity) between the synthesized compounds and HDAC2 was observed to be similar to that of MS-275.

Background: Protein tyrosine phosphatases 1B are considered to be a desirable validated target for therapeutic development of type II diabetes and obesity. Methods: A new series of imidazolyl flavonoids as potential protein tyrosine phosphatase inhibitors were synthesized and evaluated. Results: Bioactive results indicated that some synthesized compounds exhibited potent protein phosphatase 1B (PTP1B) inhibitory activities at the micromolar range. Especially, compound 8b showed the best inhibitory activity (IC50=1.0 μM) with 15-fold selectivity for PTP1B over the closely related T-cell protein tyrosine phosphatase (TCPTP). Cell viability assays indicated that 8b is cell permeable with lower cytotoxicity. Molecular modeling and dynamics studies revealed the reason for selectivity of PTP1B over TCPTP. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. Conclusion: Compound 8b should be a potential selective PTP1B inhibitor.

Background: Advanced glycation end products (AGEs) are known to be involved in the pathophysiology of diabetic complications, neurodegenerative diseases, and aging. Preventing the formation of AGEs can be helpful in the management of these diseases. Objectives: Two classes of previously synthesized traizole Schiff’s bases (4H-1,2,4-triazole-4- Schiff’s bases 1-14, and 4H-1,2,4-triazole-3-Schiff’s bases 15-23) were evaluated for their in vitro antiglycation activity. Methods: In vitro fructose-mediated human serum albumin (HSA) glycation assay was employed to assess the antiglycation activity of triazole Schiff’s bases. The active compounds were subjected to cytotoxicity analysis by MTT assay on mouse fibroblast (3T3) cell line. Molecular docking and simulation studies were carried out to evaluate the interactions and stability of compounds with HSA. Anti-hyperglycemic and antioxidant activities of selected non-cytotoxic compounds were evaluated by in vitro α-glucosidase inhibition, and DPPH free radical scavenging assays, respectively. Results: Compound 1 (IC50=47.30±0.38 μM) from 4H-1,2,4-triazole-4-Schiff’s bases has exhibited antiglycation activity comparable to standard rutin (IC50=54.5±0.05 μM) along with a stable RMSD profile in MD simulation studies. Compound 1 also exhibited a potent α-glucosidase inhibitory activity, and moderate antioxidant property. Other derivatives showed a weak antiglycation activity with IC50 values between 248.1-637.7 μM. Compounds with potential antiglycation profile were found to be non-cytotoxic in a cellular assay. Conclusion: The study identifies triazole Schiff’s bases active against fructose-mediated glycation of HSA, thus indicates their potential against late diabetic complications due to production of advancedend products (AGEs).