Identification of novel diclofenac acid and naproxen bearing hydrazones as 15-LOX inhibitors: Design,synthesis, in vitro evaluation,cytotoxicity, and in silico studies

Inflammation is the immune system's adaptive response to tissue dysfunction or homeostatic imbalance, inducing fever, pain, physiological and biochemical changes via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. NSAIDs (non-steroidal anti-inflammatory drugs), such as diclofenac acid and naproxen, are the most common inhibitors of the COX pathway. These drugs, however, are currently being studied as LOX inhibitors as well. Therefore, in the present study, a novel series of diclofenac acid and naproxen-bearing hydrazones 7(a-r) were designed, synthesized, and characterized by different spectroscopic methods like ¹H NMR, ¹³C NMR, IR and HRMS (EI) analysis. All these synthesized compounds were evaluated for their in vitro inhibitory potential against the Soybean 15-lipoxygenase (15-LOX) enzyme. These compounds exhibited varying degrees of inhibitory potential ranging from IC₅₀ 4.61 ± 3.21 μM to 193.62 ± 4.68 μM in comparison to standard inhibitors quercetin (IC₅₀ 4.84 ± 6.43 μM) and baicalein (IC₅₀ 22.46 ± 1.32 μM). The most potent compounds in the series were compounds 7c (IC₅₀ 4.61 ± 3.21 μM), and 7f (IC₅₀ 6.64 ± 4.31 μM). These compounds were found least cytotoxic and showed 96.42 ± 1.3 % and 94.87 ± 1.6 % viability to cells at 0.25 mM concentration respectively. ADME and in silico studies supported the drug-likeness and binding studies of the molecules with the target enzyme.     

Design,synthesis and biological evaluation of isoxazole-naphthalene derivatives as anti-tubulin agents

In this study, a novel series of isoxazole-naphthalene derivatives as tubulin polymerization inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against human breast cancer cell line MCF-7. Most of the synthesized compounds exhibited moderate to potent antiproliferative activity (IC₅₀ < 10.0 μM), as compared to cisplatin (15.24 ± 1.27 μM). Among them, compound 5j containing 4-ethoxy substitution at phenyl ring was found to be the most active compound with IC₅₀ value of 1.23 ± 0.16 μM. Mechanistic studies revealed that compound 5j arrested cell cycle at G2/M phase and induces apoptosis. Furthermore, in vitro tubulin polymerization assay showed that compound 5j displayed better inhibition activity on tubulin polymerization (IC₅₀ = 3.4 μM) than colchicine (IC₅₀ = 7.5 μM). Molecular docking study also revealed that compound 5j binds to the colchicine binding site of tubulin.     

Multistep synthesis and screening of heterocyclic tetrads containing furan,pyrazoline, thiazole and triazole (or oxadiazole) as antimicrobial and anticancer agents

In the present study novel heterocyclic tetrads containing furan, pyrazoline, thiazole and triazole (or oxadiazole) (1, 2, 3, 4a-e and 5a-e) were designed and synthesized and investigated for their antimicrobial (against selected bacteria and fungi) and anticancer potential. The molecules 4e and 5e containing 4-fluoro phenyl and 4-fluoro benzyl substituents showed promising antimicrobial (antibacterial and antifungal activities with MICs ranging between 0.5 and 8 µg/mL. Compounds 3 exhibited potent anticancer activity with an IC₅₀ value of 0.49 ± 1.45 µM against the human gastric cancer cell line (BGC-823) whereas compound 4e displayed an IC₅₀ value of 0.65 ± 0.53 µM against breast cancer (MCF-7) cell line respectively. All compounds showed selective toxicity against the cancer cell lines compared to human normal liver cell lines. Molecular docking studies of the most potent compounds (3 and 4e) against selected microbial and cancer proteins revealed the crucial binding interactions of the potent compounds with the target enzymes. Compounds 3 and 4e are promising lead molecules to be developed as potential drug candidates.     

Arylnaphthalide lignans from Saussurea medusa and their anti-inflammatory activities

Five new arylnaphthalide lignans (1 ? 4a/4b), together with five known analogues (5–9), were isolated from whole plants of Saussurea medusa. Compound 4 was characterized as an aryltetralin lignan with an unusual C-7′-C-9 oxygen bridge group, and a chiral HPLC analysis was carried out to afford one pair of enantiomers (4a/4b). Structures of the new compounds were elucidated by extensive spectroscopic and electronic circular dichroism (ECD) calculations. All compounds were firstly isolated from S. medusa, and compounds 1–5, 7 and 8 had never been obtained from the genus Saussurea previously. Furthermore, this is the first report of arylnaphthalide lignans isolated from S. medusa. anti-inflammatory activities of the compounds were evaluated by determining their inhibitory activities on the production of NO by LPS-stimulated RAW 264.7 cells. Compounds (?)-4a and 5 exerted the significant inhibition activities with IC₅₀ values of 13.4 ± 1.5 and 15.7 ± 1.1 μM, respectively, which even exceeded the positive control quercetin (IC₅₀ = 15.9 ± 1.2 μM). Compounds 2, (+)-4b, 6 and 9 exhibited moderate inhibitory activities with IC₅₀ values ranging from 19.7 ± 1.9 to 47.4 ± 3.1 μM. Further analysis by molecular docking showed that almost all the active compounds could interact with the amino acid residues of iNOS proteins, which also supported their anti-inflammatory activities.     

Synthesis and antimicrobial,antiproliferative and anti-inflammatory activities of novel 1,3,5-substituted pyrazoline sulphonamides

The design of novel molecules is imperative for the discovery of potent drugs in the medicinal chemistry field. In this work, new 1,3,5-substituted pyrazoline sulphonamides were synthesised using a two-step process with microwave assistance and evaluated biologically for their antimicrobial, antiproliferative, and anti-inflammatory properties. Most of the sulphonamides bearing 3-OH or 4-Cl groups exhibited significant inhibition of two Gram-positive bacteria, Bacillus subtillis and Staphylococcus aureus, and the yeast Candida albicans. Six compounds showed good activity against the cancer cell lines cervix carcinoma (Hep-2C) and human lung carcinoma (A549) with IC₅₀ in the range 16.03 ± 1.63 to 22.75 ± 0.19 μM and 18.64 ± 1.02 to 20.66 ± 2.09 μM, respectively, and exhibited low toxicity against mammalian Vero cells. In evaluating in vitro anti-inflammatory behaviour, five compounds showed high inhibition of NO production over the standard reference, with low toxicity against murine macrophage cell line RAW 264.7. Further investigation found that two compounds, 1b and 18b, exhibited the highest activity when testing mouse ear oedema. The findings are promising for the discovery of potent new drugs.     

Design,synthesis and antiviral activities of chalcone derivatives containing pyrimidine

A series of chalcone derivatives (T1-T23) containing pyrimidine were synthesized, characterized, and assessed for their antiviral activity against tobacco mosaic virus (TMV) activities. Most target compounds displayed better antiviral activities against TMV than commercial ningnanmycin. Among them, the EC₅₀ value of curative activities of compounds T1, T7, T9 and T19 (219.2, 228.2, 279.9 and 234.9 μg/mL, respectively) were superior to that of ningnanmycin (320.1 μg/mL). In addtion, the EC₅₀ value of protective activities of compounds T5, T9, T19 and T23 (235.0, 220.0, 199.5 and 187.2 μg/mL, respectively) were superior to that of ningnanmycin (307.4 μg/mL). Then, the antiviral mechanism of T19 and TMV coat protein (TMV-CP) was preliminarily investigated by microscale thermophoresis (MST) and molecular docking technology. The results showed that T19 had a strong binding affinity for TMV coat protein, and its dissociation constant (K_d) was 0.00310 ± 0.000916 μM, which was superior to ningnanmycin(0.165 ± 0.0799 μM). This study suggests that chalcone derivatives containing pyrimidine could be used as novel antiviral agents for controlling the plant viruses.     

Qingqianliusus A-N, 3,4-seco-dammarane triterpenoids from the leaves of Cyclocarya paliurus and their biological activities

Fourteen previously unreported 3,4-seco-dammarane triterpenoids named Qingqianliusus A-N (1–14), along with four known 3,4-seco-dammarane triterpenoid derivatives (15–18) were isolated from the 95 % ethanol extract of the Cyclocarya paliurus leaves. Compounds 1 and 2 possess a rare 3,11-heptacyclic lactone as natural product, and several pairs of the 3,4-seco-dammarane triterpenoid epimers with R/S configuration at C-24 were investigated and determined in detail for the first time. Compounds 8, 11, and 14 showed good α-glucosidase inhibitory effects with IC₅₀ values of 4.97 ± 0.63, 7.08 ± 0.53, and 3.76 ± 0.77 μM, respectively. Meanwhile, compound 11 was also found potent inhibition rate of 35.83 % against COX-2, as compared with the positive control celecoxib (70.28 %). In addition, compounds 3, 7, 10, and 13 exhibited outstanding cytotoxicities against human gastric cancer cell lines (BGC-823) with IC₅₀ values of 7.69 ± 0.21, 8.47 ± 0.41, 9.04 ± 0.61, and 8.86 ± 0.38 μM, respectively. Compounds 13 and 3 had modest activities on human colon cancer cell lines (HCT-116) with IC₅₀ values of 8.80 ± 0.36 and 9.45 ± 0.93 μM, respectively.     

Synthesis and anti-α-glucosidase activity evaluation of betulinic acid derivatives

In this article, a series of betulinic acid derivatives (3a ～ 3u, 4a ～ 4e) were synthesized through a stepwise structure optimization and evaluated for their anti-α-glucosidase activities. All synthesized derivatives exhibited stronger anti-α-glucosidase activities (IC₅₀: 0.56 ± 0.05 ～ 3.99 ± 0.23 μM) than betulinic acid (IC₅₀: 7.21 ± 0.58 μM) and acarbose (IC₅₀: 611.45 ± 15.51 μM). Compound 3q presented the outstanding inhibitory activity (IC₅₀: 0.56 ± 0.05 μM), which was ～ 1100 time stronger than that of acarbose. Compound 3q was revealed as a reversible and noncompetitive α-glucosidase inhibitor by inhibitory mechanism assay. Fluorescence spectra, 3D fluorescence and CD spectra results showed that the interaction of compound 3q with α-glucosidase caused the conformational and secondary structure content change of α-glucosidase. Finally, the molecular docking simulated the interaction between compound 3q with α-glucosidase and the physicochemical parameter was assessed using SwissADME software.     

Synthesis,anticancer evaluation,and molecular modeling study of new 2-(phenylamino)pyrazolo[1,5-a]pyrimidine analogues

The reaction of 3-amino-5-phenylaminopyrazoles 2 with 3-(dimethylamino) acrylonitrile derivatives resulted in a series of substituted pyrazolopyrimidine analogues 4 and 6. The DFT studies of the isolated compounds showed that the frontier molecular orbitals energy gap was close and in the 2.65–2.81 eV range where the derivative 6b has the lowest and both of 4a and 4c have the highest values. Meanwhile, the anticancer activity of the newly synthesized pyrazolopyrimidine analogues have been tested against several different cell lines (MCF-7, PC3, Hep-2 and WI38). The investigated pyrazolopyrimidines showed remarkable cytotoxicity activity against the MCF-7 and Hep-2 cell lines. In comparison to the effects of 5-fluorouracil, IC₅₀ = 10.19 ± 0.42 and 7.19 ± 0.47, compounds 6a-c demonstrated potential anticancer activity with IC₅₀ values for MCF-7 (10.80 ± 0.36–19.84 ± 0.49 μM) and Hep-2 (8.85 ± 0.24–12.76 ± 0.16 μM). Important details regarding the protein's binding sites were disclosed when the produced analogues docked with the crystal structure of the KDM5A protein, which was located in the protein data library.     

Synthesis of Substituted Quinolinyl Ether‐based Inhibitors of PI3K as Potential Anticancer Agents

A new strategy for the preparation of 8‐quinolyl ethers 3 ( a – g ), 5 ( a – g ), and 7 ( a – d ) was studied by copper (II)‐catalyzed methodology in the presence of Cs₂CO₃ and acetone–water mixture (1:1). Screening of quinolinyl‐8‐ethers was investigated against anticancer expressive studies to validate new chemical entity in medicinal chemistry. Approaches were evaluated against breast cancer (MCF‐7), skin cancer (G‐361), and colon cancer (HCT 116) cell lines. Inhibitory potentials against phosphoinositide‐3‐kinase (PI3K) enzyme responsible for cancer development have been evaluated by competitive ELISA studies. In PI3K assay, 3a – c were inactive (IC₅₀ > 5 μM), while 3e – g , 5a , 5c – e , 5g , 7a , and 7d showed a moderate activity (IC₅₀ ≥ 0.05 μM). Compounds ( 5b , 5f , 7b , and 7c ) showed significant activity (IC₅₀ < 1.0 μM); thus, their anticancer activities were carried out. Anticancer activity was found to be selective towards breast cancer (MCF‐7); 5b , 5f , 7b , and 7c showed predominant relative percentage activities of 74.12%, 79.04%, 72.56%, and 78.47%, with IC₅₀ values of 5b (2.27 ± 0.88 μM), 5f (1.38 ± 0.60 μM), 7b (2.64 ± 0.86 μM), and 7c (1.87 ± 0.68 μM) compared with the standard doxorubicin 73.14% inhibition (IC₅₀ = 1.98 ± 0.75 μM). Docking study also conducted to find out the binding interactions with p110α (PDB ID: 3T8M) enzyme. Compounds 5b , 5f , 7b , and 7c showed best docking score into the active site of PI3K 12.59, 10.51, 56.52, and 8.61 nM. Structure–activity relationship studies demonstrated that the synthesized compounds are the potential PI3K inhibitors to treat various cancer‐related diseases.     

Synthesis, α-glucosidase inhibition and molecular docking studies of natural product 2-(2-phenyethyl)chromone analogues

A series of natural product (2-phenyethyl)chromone analogues (3–34) were designed, synthesized, and screened for their α-glucosidase inhibitory activity. The results indicated that some of the synthesized derivatives displayed inhibitory activities against α-glucosidase with IC₅₀ values ranging from 11.72 ± 0.08 to 85.58 ± 2.30 μM when compared to the standard drug acarbose (IC₅₀ = 832.22 ± 2.00 μM). Among them, compound 4 with a hydroxyl group at the 7-position of chromone and a chloro group at the 4-position of the benzene ring, displayed the most significant inhibitory activity with the IC₅₀ value of 11.72 ± 0.08 μM. The inhibitory mechanism of compound 4 against α-glucosidase was studied by enzyme kinetic, circular dichroism spectra, fluorescence quenching, and molecular docking. Sucrose loading test in vivo further demonstrated that it could decrease blood glucose levels after sucrose administration in normal Kunming mice. In vitro cytotoxicity showed that 4 exhibited low cytotoxicity against normal human cell lines. The ADME study suggested that all compounds are likely to be orally active as they obeyed Lipinski’s rule of five. In summary, our studies showed that these derivatives are a new class of α-glucosidase inhibitors.     

Synthesis of new 1,2-disubstituted benzimidazole analogs as potent inhibitors of β-Glucuronidase and in silico study

New benzimidazole analogues (1–18) were synthesized and characterized through different spectroscopic techniques such as ¹H NMR, ¹³C NMR and HREI-MS. All analogues were screened for β-glucuronidase inhibitory potential. All analogues showed varied degree of inhibitory potentials with IC₅₀ values ranging between 1.10 ± 0.10 to 39.60 ± 0.70 μM when compared with standard _D-saccharic acid-1,4- lactone having IC₅₀ value 48.30 μM. Analogues 17, 11, 9, 6, 1 and 13 having IC₅₀ values 1.10 ± 0.10, 1.70 ± 0.10, 2.30 ± 0.10, 5.30 ± 0.20, 6.20 ± 0.20 and 8.10 ± 0.20 μM respectively, showed excellent β-glucuronidase inhibitory potential many folds better than the standard. All other analogues also showed good inhibitory potential better as compared to standard. Structure activity relationships (SAR) has been established for all compounds. The results from molecular docking studies supports the established SAR and developed a strong correlation with the results from in to vitro assay. The molecular docking results clearly highlighted how substituents like nitro and chloro affect the binding position of the active compounds in the active site. The docking results were also used to properly establish the effect of bulky substituents of least active compounds on reduced β-glucuronidase inhibitory activity. Compounds 1–18 were found non-toxic.     

Synthesis,and biological screening of chloropyrazine conjugated benzothiazepine derivatives as potential antimicrobial,antitubercular and cytotoxic agents

A series of twenty new chloropyrazine conjugated benzothiazepines (22–41) have been synthesized with 58%–95% yields. The compounds were characterized by using different spectroscopic techniques including FT-IR, ¹H NMR, ¹³C NMR spectroscopy and mass spectrometry. The synthesized compounds (22–41) and their precursor chalcones (2–21) were evaluated for antitubercular and cytotoxic activities. Additionally, compounds 22–41 were also tested for antimicrobial activity. Among the chalcone series (2–21), compounds 7 and 14 showed significant antitubercular activities (MICs 25.51 and 23.89 µM, respectively), whereas among benzothiazepines (22–41), compounds 27 and 34 displayed significant antimicrobial (MICs 38.02 µM, 19.01 µM) and antitubercular (MIC 18.10 µM) activities. Compounds 7 and 41 displayed cytotoxic activities with IC₅₀ of 46.03 ± 1 and 35.10 ± 2 µM respectively. All the compounds were evaluated for cytotoxic activity on normal human liver cell lines (L02) and found to be relatively less selective towards this cell line. The most active compounds identified through this study could be considered as potential leads for the development of drugs with possible antimicrobial, antitubercular, and cytotoxic activities.     

Design,synthesis, bioactivity and mechanism of action of novel myricetin derivatives containing amide and hydrazide

A series of myricetin derivatives containing amide and hydrazide were designed and synthesized. All the compounds were characterized by NMR and HRMS. Bioactivity test showed that some of the target compounds had excellent anti-tobacco mosaic virus (TMV) activity. In particular, the median effective concentration (EC₅₀) values of the anti-TMV curative and protective activities of N-(2-(2-(2-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)acetyl)hydrazineyl)-2-oxoethyl)-4-(trifluoromethyl)benzamide (G9) were 202.3 and 164.0 μg/mL respectively, superior to ningnanmycin (329.1, 230.3 μg/mL). Microscale thermophoresis (MST) and molecular docking showed that G9 had an excellent binding affinity with tobacco mosaic virus coat protein (TMV-CP) (K_d = 0.158 ± 0.024 μM), which was better than that of ningnanmycin (K_d = 2.074 ± 0.818 μM). Moreover, there were many interaction forces between G9 and the key amino acid residues of TMV-CP. The chlorophyll content and peroxidase (POD) activity of tobacco leaves treated with G9 increased significantly, indicating that G9 could improve the photosynthesis of tobacco leaves and stimulate the resistance of tobacco leaves to TMV. The insecticidal activity of G9 against Mythimna separata (M. separate) was found to be 95.2% at 200 μg/mL, which was close to bufenozide (100%). The insecticidal activity of myricetin was significantly improved after the introduction of active groups of amide and hydrazide, which could be further explored.     

Design,Synthesis, and Pharmacological Assay of Novel Compounds Based on Pyridazine Moiety as Potential Antitumor Agents

In an endeavor to develop antitumor agents, we made a credible survey regarding synthesis, structure, and pharmacological assay of novel pyridazine derivatives, so that 2‐((6‐(4‐chloro‐3‐methylphenyl)pyridazin‐3‐yl)oxy)acetohydrazide 3 was utilized as scaffold to build novel compounds 4 – 19 by reaction with various electrophilic reagents, followed by determination and explanation atropisomerism phenomena and tauomerism ratio such as keto‐enol and lactam–lactim tautomers for some synthesized compounds. In vitro, these compounds were screened for antitumor efficacy versus two cell lines, namely, hepatocellular carcinoma and mammary gland breast cancer, by using MTT assay. Among the examined compounds, compound 16 was exhibited promising potent activity (IC₅₀ = 8.67 ± 0.7 μM) versus HepG2 cell line. Meanwhile, compounds 3 and 16 were manifested the very highest efficacy (IC₅₀ = 5.68 ± 0.6 and 9.41 ± 0.9 μM) versus MCF‐7 cell line.     

Design,synthesis, biological evaluation and in silico studies of novel 1,2,3-triazole linked benzoxazine-2,4-dione conjugates as potent antimicrobial,antioxidant and anti-inflammatory agents

In an attempt to rationalize the search for new potential anti-inflammatory and anti-infection agents, a new series of 1,4-and 1,5-disubstituted 1,2,3-triazoles linked benzoxazine conjugates have been synthesized via “Click Chemistry” reaction, were designed, synthesized and characterized by means of spectral and elemental data. The newly synthesized compounds have been assessed for their antimicrobial, antioxidant and anti-inflammatory potential. Results revealed that all synthesized compounds display superior activities to the standard drug against different bacterial strains especially S. aureus, M. luteus, and P. aeruginosa, with good to moderate activity towards the tested E. coli bacteria, in respect to the commercial antibiotic, tetracycline. Moreover, the antifungal activity was screened against C. albicans and C. krusei yeasts and results demonstrate potent activity as compared to the standard drug, ampicillin. The antioxidant activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays, whose results indicate that analogues 4a (IC₅₀ 1.88 ± 0.07 µM and 2.17 ± 0.02) followed by 4b (IC₅₀ 2.19 ± 0.09 µM and 2.38 ± 0.43 µM), 4d (IC₅₀ 2.30 ± 0.01 µM and 4.07 ± 0.57 µM), and 4f (2.98 ± 0.02 µM and 3.80 ± 0.01 µM), respectively, exhibited the strongest activity when compared to the standard reference, butylated hydroxytoluene (BHT) (3.52 ± 0.08 µM and 4.64 ± 0.11 µM). In addition, their anti-inflammatory activity was assessed using the xylene-induced ear edema standard technique and the results demonstrated the potency of 4a, 4b and 4d as excellent anti-inflammatory agents. Preliminary structure–activity relationship studies (SARs) provide those biological activities can be modulated by the presence of unsubstituted aromatic ring as well as the position of substituents on the phenyl moiety via electron withdrawing groups (EWGs) or electron donating groups (EDGs) effects. Docking studies on the most promising compounds 4a, 4b, and 4d into the active sites of S. aureus tyrosyl-tRNA synthetase, Candida albicans N-Myristoyltransferase, Human COX-2 enzyme, and Human Peroxiredoxin 5 revealed good binding profiles with the target proteins. The interaction's stability was further assessed using a conventional atomistic 100 ns dynamic simulation study. Hence, our results recommended the rationalized targets 4a, 4b and 4d, to be promising lead candidates for the discovery of novel dual anti-inflammatory and anti-infection agents.     

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.     

Synthesis,in vitro evaluation,and molecular docking studies of benzofuran based hydrazone a new inhibitors of urease

This work has described the synthesis of novel class (1–25) of benzofuran based hydrazone. The hybrid scaffolds (1–25) of benzofuran based hydrazone were evaluated in vitro, for their urease inhibition. All the newly synthesized analogues (1–25) were found to illustrate moderate to good urease inhibitory profile ranging from 0.20 ± 0.01 to 36.20 ± 0.70 µM. Among the series, compounds 22 (IC₅₀ = 0.20 ± 0.01 µM), 5 (IC₅₀ = 0.90 ± 0.01 µM), 23 (IC₅₀ = 1.10 ± 0.01 µM) and 25 (IC₅₀ = 1.60 ± 0.01 µM) were found to be the many folds more potent than thiourea as standard inhibitor (IC₅₀ = 21.86 ± 0.40 µM). The elevated inhibitory profile of these analogues might be due to presence of dihydroxy and flouro groups at different position of phenyl ring B attached to hydrazone skeleton. These dihydroxy and fluoro groups bearing compounds have shown many folds better inhibitory profile through involvement of oxygen of dihydroxy groups in hydrogen bonding with active site of enzymes. Various types of spectroscopic techniques such as ¹H-, ¹³C- NMR and HREI-MS spectroscopy were used to confirm the structure of all the newly developed compounds. To find SAR, molecular docking studies were performed to understand, the binding mode of potent inhibitors with active site of enzymes and results supported the experimental data.     

Potential enzyme inhibitor triazoles from aliphatic esters: Synthesis,enzyme inhibition and docking studies

Enzyme inhibitors are vital aspects for studying enzymes and are employed as drugs to treat certain disorders, thus implying pivotal role in drug discovery. In the current study, a series of triazole compounds 4(a-o) were synthesised to explore their inhibitory potential against α-glucosidase and urease enzymes. These derivatives with dichlorophenyl substituents were prepared by cyclization of thiosemicarbazides and their structures were confirmed through spectroanalytical techniques. The in vitro biological screening revealed that the compounds 4a, 4b, 4k, 4l, 4m, 4o having IC₅₀ values of 121.09 ± 1.25, 137.22 ± 0.22, 110.4 ± 2.4, 114.79 ± 1.1, 146.72 ± 1.29, 94.21 ± 0.15 [µM] respectively, exhibited good potential α-glucosidase inhibition, in comparison to Acarbose: IC₅₀ 51.23 µM, while the compounds 4a, 4b, 4c, 4k, 4l, having IC₅₀ values of 48.52 ± 0.39, 52.22 ± 1.37, 60.98 ± 0.34, 37.06 ± 0.51, 38.66 ± 1.7 [µM] respectively exhibited good potential for urease inhibition near to standard(Thiourea: IC₅₀ 24.14 [µM]). These in vitro findings were accompanied further by molecular docking simulations, which revealed significant binding interactions of the synthesized derivatives within the active sites of the enzymes.     

Antitubercular and antioxidant activities of hydroxy and chloro substituted chalcone analogues: Synthesis,biological and computational studies

A series of chalcone analogues (1–15) were synthesized by Claisen-Schmidt condensation in good yields (70–95%) and characterized by FT-IR, ¹H NMR and mass spectral methods. Additionally, compounds 3 and 7 were characterized by ¹³C NMR. Antitubercular and antioxidant activities of the chalcones were evaluated by MABA and DPPH free radical assays. In MABA assay analogues 3 (MIC = 14 ± 0.11 µM) and 11 (MIC = 14 ± 0.17 µM) bearing fluorine and methoxy groups at para and meta positions were 1.8-times more active than the standard pyrazinamide (MIC = 25.34 ± 0.22 µM). The chalcone analogues such as compound 7 (IC₅₀ = 4 ± 1 µg/mL) containing electron releasing groups such as OH at ortho position had slightly more antioxidant activity than Gallic acid (IC₅₀ = 5 ± 1 µg/mL). The potential compounds 3, 7, 9 and 11 were less selective and toxic against human live cell lines-LO2. Further, molecular docking results of chalcones against anti-tubercular drug target isocitrate lyase (PDB ID: 1F8M) revealed that compound 3 and 11 shown least binding energies as ?7.6, and ?7.5 kcal/mol are in line with in vitro MABA assay, suggesting that these compounds 3 and 11 are strong inhibitor of isocitrate lyase. SwissADME programme estimated the drug likeliness properties of compounds 3, 7, 9 and 11. The lead molecules arisen through this study helps to develop new antitubercular and antioxidant agents.