Green synthesis,antibacterial, antiviral and molecular docking studies of α-aminophosphonates

Abstract

An efficient method for the synthesis of α-aminophosphonate derivatives has been developed with different functional groups under catalyst and solvent free conditions at room temperature in both conventional and ultrasonication methods. Ultrasonication method offers excellent yields within shorter reaction times. All the title compounds 4a–l were tested for their antibacterial, antiviral activity using Gram-positive bacteria (Staphylococcus aureus, and Bacillus subtilis), Gram-negative bacteria (Klebsiella pneumoniae and Escherichia coli) and NDV infected embryonated eggs (in ovo) and NDV infected BHK-21 cell lines (in vitro) respectively. Besides, molecular docking studies were also carried out to the title compounds against Hemagglutinin-neuramidase enzyme to determine the therapeutic binding efficacy of the ligands synthesized. The results indicated that, among the title compounds, compounds such as 4f, 4l, 4k, 4b, 4i and 4h have shown high content of antibacterial and antiviral activity than the rest of the compounds and the level activity was high when compared to the standard, ribavirin. Based on the results, it is concluded that, the reported α-aminophosphonates will open new vistas and stands as a new generation of antiviral and antibacterial drug candidates in future.     

Biology-oriented drug synthesis of nitrofurazone derivatives: Their α-glucosidase inhibitory activity and molecular docking studies

In the present study, twenty (20) structural variants of nitrofurazone were synthesized based on BIODS (Biology-oriented drug synthesis) approach. The structure elucidation of the synthetic molecules (1–20) was carried out using different spectroscopic techniques, and their α-glucosidase inhibitory activity was also determined. The synthetic molecules 1–20 exhibited good α-glucosidase inhibition than the parent, nitrofurazone. Four compounds 2, 4, 6, and 7 showed potential inhibition against α-glucosidase with IC₅₀ values ranging between 0.63 ± 0.25–1.29 ± 0.46 µM as compared to the standard acarbose (IC₅₀ = 2.05 ± 0.41 µM). Nevertheless, compounds 15 (IC₅₀ = 0.74 ± 0.12 µM), and 19 (IC₅₀ = 0.54 ± 0.3 µM) also displayed good α-glucosidase inhibition and compound 19 was the most active compound of the series. Kinetic study of the active compounds 7 and 19 was also carried out to confirm the mode of inhibition. The binding interactions of the most active compounds within the active site of enzyme were determined by molecular docking. Moreover, molecular dynamic simulation of compound 19 was also performed in order to determine the stability of the overall complex (α-glucosidase + c19) in an explicit watery environment. The synthetic molecules were predicted as non-cytotoxic, however, seven compounds 1, 3, 4, 9, 10, 11, and 12 were predicted as carcinogenic.     

Total synthesis of the natural product (±)-dibromophakellin and analogues

(±)-Dibromophakellin has been synthesized in two steps from a known alkene intermediate. The key step in the synthesis is the NBS olefin activation to facilitate the addition of a guanidine molecule across the double bond.     

Synthesis,antibacterial activity,and docking studies of some novel N′-benzylidene-2-(2,4,5-trifluorophenyl)acetohydrazides

Research on Chemical Intermediates - An improved method was developed for synthesis of 2,4,5-trifluorobenzohydrazide derivatives through condensation of trifluorophenylacetohydrazide with different...     

Three novel Cu(II), Cd(II) and Cr(III) complexes of 6−Methylpyridine−2−carboxylic acid with thiocyanate: Synthesis,crystal structures,DFT calculations,molecular docking and α-Glucosidase inhibition studies

Novel complexes of 6?methylpyridine?2?carboxylic acid and thiocyanate {[Cu(NCS)(6-mpa)₂], (1); [Cd(NCS)(6-mpa)]_n, (2); [Cr(NCS)(6-mpa)₂·H₂O], (3)} were synthesized, and their structures were characterized by XRD analysis, FT–IR and UV–Vis spectroscopic techniques. The inhibitory activities of the synthesized complexes (1–3) on α-glucosidase were determined by using genistein reference compound. Furthermore, the optimized geometry and vibrational harmonic frequencies for the complexes 1–3 were obtained by DFT/HSEh1PBE/6–311G(d,p)/LanL2DZ level. Electronic spectral properties were examined by using TD-DFT/HSEh1PBE/6–311G(d,p)/LanL2DZ level with CPCM model. Additionally, major contributions to the electronic transitions were determined via Swizard program. The refractive index, linear optical and non?nonlinear optical parameters of the complexes 1–3 were investigated at HSEh1PBE/6–311G(d,p) level. The docking studies of the complexes 1–3 to the binding site of the target protein (the template structure S. cerevisiae isomaltase are fulfilled. Lastly, natural bond orbital analysis was used to investigate inter- and intra-molecular bonding and interaction among bonds.     

Synthesis,antioxidant activity,and α-glucosidase enzyme inhibition of α-aminophosphonate derivatives bearing piperazine-1,2,3-triazole moiety

A novel series of piperazine-1,2,3-triazole bearing dimethyl(((2-(4-((1H-1,2,3-triazole-4-yl)methyl)piperazin-1-yl)ethylamino)(2-hydroxyaryl)methyl)phosphonate derivatives have been prepared via copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) (Click Reaction) and Schiff base reactions. The synthesized compounds were confirmed by spectral characterization (¹H, ¹³C and ³¹P NMR, and mass). The title compounds were evaluated for in vitro alpha glucosidase enzyme inhibition and in vitro antioxidant activity using DPPH and H₂O₂ methods.     

Design, synthesis and molecular docking studies of novel triazole antifungal compounds

Based on the active site of Candida albicans lanosterol 14α-demethylase (CACYP51), novel triazole compounds structurally different from the current triazole drugs were designed and synthesized. In vitro antifungal activities showed that compounds 10,11, 16 and 20 exhibited strong activities. In addition, compounds 10,11 and 16 also displayed certain activities against fluconazole-resistant fungi.     

Identification of novel oxadiazole-based benzothiazole derivatives as potent inhibitors of α-glucosidase and urease: Synthesis,in vitro bio-evaluation and their in silico molecular docking study

This research work represents a synthetic approach for the development of hybrids derivatives of oxadiazole-based benzothiazole (1–17) and diversity in derivatives was achieved using variety of aryl ring of S-substituted benzothiazole to see the effect on the biological activities. All the synthesized derivatives were evaluated for their in vitro α-glucosidase and urease inhibitory potential. The α-glucosidase and urease inhibition profile of the new derivatives represents moderate to good inhibitory potential with IC₅₀ values ranging from 4.60 ± 1.20 µM to 48.40 ± 7.70 µM (α-glucosidase) and 8.90 ± 2.80 to 57.30 ± 7.70 µM (urease) respectively. The results were compared to standard acarbose (38.60 ± 4.50 µM) and thiourea (58.70 ± 6.80 µM) drugs respectively. Among the synthesized series, the analogs 1 having IC₅₀ values of and 4.60 ± 1.20 (α-glucosidase), 8.90 ± 2.80 (urease) and 2 with IC₅₀ values of 5.60 ± 1.60 (α-glucosidase) and 10.90 ± 2.10(urease) were found to be significantly active against targeted α-glucosidase and urease enzymes. The structure of all the newly synthetics scaffolds were confirmed by using different types of spectroscopic techniques such as HREI-MS, ¹H- and ¹³C- NMR spectroscopy. The molecular docking studies of the synthesized derivatives showed good correlations with the experimental findings. The binding modes of active compounds and their interactions with active site residues revealed them as possible anti-diabetics and anti-urease leads. The degree of activity and docking studies displayed by the novel innovative structural hybrids of oxadiazole-based benzothiazole moieties make these compounds new active leads and promising candidates for the development of anti-diabetics and anti-urease agents.     

Synthesis and biological evaluation of carbohydrate appended hydrazinocyclopentenes with potent glycation and α-glucosidase inhibition activities

Synthesis and biological evaluation of novel alkylidenecyclopentene glycohybrids via palladium and click chemistry are described. Out of the six molecules synthesized, four molecules were screened against α-glucosidase, α-amylase, and glycation reactions. The results showed that the compound 7f with a galactose appendage is a good α-glucosidase inhibitor and a potent anti-glycation agent under in vitro conditions with an IC₅₀ value of 0.075 μM and 0.022 μM, respectively. The toxicity of the compounds against normal cell lines was checked by MTT assay.     

Synthesis and properties of α, α′ -bis -(p-benzylphenyl)xylene

Summary ,-bis-(p-Benzylphenyl)xylene was synthesized for the first time and its UV and infrared spectra determined.     

Benzoylquinazolinone derivatives as new potential antidiabetic agents: α-Glucosidase inhibition,kinetic, and docking studies

Benzoylquinazolinone derivatives 3a–n were synthesized via a simple one-step reaction, and evaluated for in vitro α-glucosidase inhibitory activity. Compounds 3d , 3f–g , 3i , and 3m–n showed more inhibitory activity than standard drug acarbose (IC₅₀ = 750.0 ± 1.5 μM), and among them, compound 3d displayed the highest α-glucosidase inhibitory activity (IC₅₀ = 261.6 ± 0.1 μM). The kinetic analysis of the compound 3d revealed that this compound inhibited α-glucosidase in a competitive manner (K_i = 255 μM). The docking studies were applied to predict binding modes of the synthesized compounds in active site of α-glucosidase.     

C-methyl flavonoid from the leaves of Cleistocalyx conspersipunctatus: α-glucosidase inhibitory,molecular docking simulation and biosynthetic pathway

We extracted one new C-methyl flavonoid, farrerol 7-O-β-d-(6-O-galloyl)glucopyranoside (1), along with 11 known flavonoids, from the Cleistocalyx (C.) conspersipunctatus leaves. Elucidation of these flavonoid structures was accomplished through spectroscopic investigation and electronic circular dichroism (ECD) computation. Compared to corosolic acid (IC₅₀: 15.5 ± 0.9 μM), an established inhibitor, the compound 1 (IC₅₀: 6.9 ± 1.2 μM) was found more active in suppressing α-glucosidase. These findings imply the potential of compound 1 as a valid α-glucosidase inhibitor, which also offer evidence for future animal experiments and clinical trials. Besides, molecular docking was employed to explore the probable mechanism for α-glucosidase–compound 1 interaction. The biosynthetic pathway of these flavonoids in C. conspersipunctatus were proposed.     

Synthesis,anticancer activity,toxicity evaluation and molecular docking studies of novel phenylaminopyrimidine—(thio)urea hybrids as potential kinase inhibitors

Thirty-two novel urea/thiourea compounds as potential kinase inhibitor were designed, synthesized and evaluated for their cytotoxic activity on breast (MCF7), colon (HCT116) and liver (Huh7) cancer cell lines. Compounds 10, 19 and 30 possessing anticancer activity with IC₅₀ values of 0.9, 0.8 and 1.6 μM respectively on Huh7 cells were selected for further studies. These hit compounds were tested against liver carcinoma panel. Real time cell electronic sensing assay was used to evaluate the effects of the compounds 10, 19 and 30 on the growth pattern of liver cancer cells. Apoptotic cell death and cell cycle analysis upon treatment of liver carcinoma cells with hit compounds were determined. A significant apoptotic cell death was detected upon treatment of Huh7 and Mahlavu cells with compound 30 after 48 h of treatment. Additionally, compound 10 caused cell cycle arrest at G0/G1 phase. Mutagenicity of hit compounds was evaluated. Assertively, these compounds were not found to be mutagenic on Salmonella typhimurium strains TA98 and TA100. To understand the binding modes of the synthesized compounds, molecular docking studies were performed using the crystal data of VEGFR and Src-kinase enzymes in correlation with anticancer activities.     

Screening and docking studies of natural phenolic inhibitors of carbonic anhydrase Ⅱ

Carbonic anhydrase Ⅱ (CAⅡ) is an important enzyme complex with Zn2+,which is involved in many physiological and pathological processes, such as calcification, glaucoma and tumorigenicity. In order to search for novel inhibitors of CAⅡ, inhibition assay of carbonic anhydrase Ⅱ was performed, by which seven natural phenolic compounds, including four phenolics (grifolin, 4-O-methyl-grifolic acid, grifolic acid, and isovanillic acid) and three flavones (eriodictyol, quercetin and puerin A), showed in-hibitory a...     

Dicyanoanilines as potential and dual inhibitors of α-amylase and α-glucosidase enzymes: Synthesis,characterization, in vitro,in silico,and kinetics studies

The present study comprised of the synthesis of dicyanoaniline derivatives of pyridine, thiophene, furan, and substituted phenyl 1–29. All synthetic derivatives were evaluated for their potential to inhibit α-amylase and α-glucosidase enzymes. The synthesized compounds are classified into three categories A, B, and C based on variable substituents at R₁ and R_2, and the structure–activity relationship was discussed accordingly. Amongst twenty-nine derivatives, 1–29, five compounds 2, 9, 18, 23, and 24 displayed excellent inhibition against α-amylase and α-glucosidase enzymes with the IC₅₀ values ranging between 20.33 ± 0.02–25.50 ± 0.06 µM and 21.01 ± 0.12–27.75 ± 0.17 µM, respectively, while other compounds showed moderate to weak inhibition against both enzymes. Acarbose was used as the positive control in this study. The enzyme kinetic studies showed non-competitive and un-competitive types of inhibition mechanism against α-amylase and α-glucosidase enzymes, respectively. In silico studies have demonstrated the involvement of these molecules in numerous binding interactions within the active site of the enzyme.     

Synthesis and inhibition profiles of N-benzyl- and N-allyl aniline derivatives against carbonic anhydrase and acetylcholinesterase – A molecular docking study

The alkyl and aryl derivatives of aniline are important starting materials in fine organic synthesis. Allyl bromide and benzyl chloride were taken as substrates for the alkylation reaction and as a halide ion scavenger. Triethylamine was utilized at reflux condition of N,N-dimethylacetamide (DMA). Novel synthesized N-benzyl and N-allyl aniline derivatives (1a-f) were evaluated to be highly potent inhibitors for acetylcholinesterase (AChE) and carbonic anhydrases (hCAs). The half maximal inhibitory concentration (IC₅₀) of N-benzyl- and N-allyl aniline derivatives were calculated between 243.11 and 633.54 nM for hCA I, 296.32–518.37 nM for hCA II and 182.45–520.21 nM for AChE enzymes. On the other hand, K_i values are in the range of 149.24 ± 15.59 to 519.59 ± 102.27 nM for AChE, 202.12 ± 16.21 to 635.31 ± 45.33 nM for hCA I and 298.57 ± 94.13 to 511.18 ± 115.98 nM for hCA II isoenzyme. Additionally, in silico molecular docking computations were performed with Autodock Vina program to support the experimental in vitro studies for both hCAs and AChE inhibitors. The in silico molecular docking results demonstrated that the scores are in good agreement with the experimental results.     

Synthesis,characterization, molecular and supramolecular structures of nickel(II) complexes derived from α-diketone and α-ketoaldehyde bisaroylhydrazones

A new series of nickel(II) complexes derived from symmetrical diacetyl bisaroylhydrazones [Ni(L¹-R)] and unsymmetric phenylglyoxal bisaroylhydrazones [Ni(L²-R)] have been prepared and characterized. X-ray crystal and molecular structures of [Ni(L¹-H)], [Ni(L¹-pCH₃O)] and [Ni(L¹-pNO₂)] have been determined. In these complexes, the Ni(II) is in a distorted square planar environment and the aroylhydrazone acts as dinegative tetradentate ligand forming a 5,5,5-tricyclic chelate ring. Reaction of [Ni(L¹-R)] with aqueous ammonia afforded the paramagnetic five coordinate [Ni(L¹-R)(NH₃)] while [Ni(L²-R)] gave the diamagnetic square planar [Ni(L²-R)(NH₃)] complexes. Reaction of [Ni(L¹-R)] complexes with imidazole gave the corresponding paramagnetic octahedral bis(imidazole) adducts. X-ray structures of both [Ni(L¹-H)(HIm)₂] and [Ni(L¹-pNO₂)(HIm)₂] suggest a distorted octahedral structure where the bisaroylhydrazone occupies the basal plane while the two imidazoles occupy the axial sites. The molecular units are associated together forming triple stranded helical chains. With imidazole the [Ni(L²-R)] series gave the corresponding diamagnetic mono(imidazole) [Ni(L²-R)(HIm)] complexes, The X-ray structure of {Ni(L²-pCH₃)(HIm)] suggest square planar arrangement around the Ni(II) where the bisaroylhydrazone acts as dinegative NNO tridentate ligand forming with the Ni(II) a 5,6-bicyclic chelate ring the fourth coordination site is occupied by imidazole nitrogen.     

Synthesis and α-glucosidase inhibitory activity of chrysin,diosmetin, apigenin,and luteolin derivatives

Several derivatives have been synthesized from chrysin, diosmetin, apigenin, and luteolin, which were isolated from diverse natural plants. The α-glucosidase inhibitory activity of these compounds was evaluated. The glucosidase inhibitory activity of all derivatives （IC50 〈 24.396 μmol]L） was higher compared with that of the reference drug, acarbose （IC50=563.601 ±40.492μmol/L）, and 1- deoxynojirimycin （IC50 = 226.912± 12.573 μmol/L）. O3＇,O7-Hexyl diosmetin （IC50 = 2.406 ± 0.101μmol/L） was the most potent inhibitor identified. These compounds showed a higher inhibitory ability compared with their precursors except the luteolin derivatives. In general, the inhibitory activity of the synthetic derivatives was enhanced with long alkyl chains at positions 3＇, 4＇ and 7 of the flavonoid.     

Design,synthesis and exploration of in silico α-amylase and α-glucosidase binding studies of pyrrolidine-appended quinoline-constrained compounds

Research on Chemical Intermediates - A series of new pyrrolidine-appended phenoxy-substituted quinoline derivatives were synthesized using 2-chloro-3-formyl quinoline. Initially, the second...     

Synthesis and evaluation of eight- and four-membered iminosugar analogues as inhibitors of testicular ceramide-specific glucosyltransferase, testicular β-glucosidase 2, and other glycosidases

Eight- and four-membered analogues of N-butyldeoxynojirimycin (NB-DNJ), a reversible male contraceptive in mice, were prepared and tested. A chiral pool approach was used for the synthesis of the target compounds. Key steps for the synthesis of the eight-membered analogues involve ring-closing metathesis and Sharpless asymmetric dihydroxylation and for the four-membered analogues Sharpless epoxidation, epoxide ring-opening (azide), and Mitsunobu reaction to form the four-membered ring. (3S,4R,5S,6R,7R)-1-Nonylazocane-3,4,5,6,7-pentaol (6) was moderately active against rat-derived ceramide-specific glucosyltransferase, and four of the other eight-membered analogues were weakly active against rat-derived β-glucosidase 2. Among the four-membered analogues, ((2R,3S,4S)-3-hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (25) displayed selective inhibitory activity against mouse-derived ceramide-specific glucosyltransferase and was about half as potent as NB-DNJ against the rat-derived enzyme. ((2S,4S)-3-Hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (27) was found to be a selective inhibitor of β-glucosidase 2, with potency similar to NB-DNJ. Additional glycosidase assays were performed to identify potential other therapeutic applications. The eight-membered iminosugars exhibited specificity for almond-derived β-glucosidase, and the 1-nonylazetidine 25 inhibited α-glucosidase (Saccharomyces cerevisiae) with an IC(50) of 600 nM and β-glucosidase (almond) with an IC(50) of 20 μM. Only N-nonyl derivatives were active, emphasizing the importance of a long lipophilic side chain for inhibitory activity of the analogues studied.