Sulfonate and sulfamate derivatives possessing benzofuran or benzothiophene nucleus as potent carbonic anhydrase II/IX/XII inhibitors

In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a–t, having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH₂, NHMe, or NMe₂) was designed and synthesized. Most of the derivatives exhibited higher potency than acetazolamide as inhibitors of the purified hCAII, IX and XII isoforms. The most potent inhibitors for hCAII, hCAIX and hCAXII were 1g, 1b and 1d with an IC₅₀ ± SEM values of 0.14 ± 0.03, 0.13 ± 0.03 and 0.17 ± 0.06 µM, respectively. In addition, compounds 1d and 1n exerted preferential inhibitory effect against hCAXII isozyme with good potencies. Some selected compounds were docked within the active pocket of these isozymes and binding of the molecules revealed that sulfonate and sulfamate rings were located towards the active cavity and compounds coordinated to zinc ions.     

Design and synthesis of new fused carbazole-imidazole derivatives as anti-diabetic agents: In vitro α-glucosidase inhibition,kinetic, and in silico studies

Twenty three fused carbazole–imidazoles 6a–w were designed, synthesized, and screened as new α-glucosidase inhibitors. All the synthesized fused carbazole-imidazoles 6a-w were found to be more active than acarbose (IC₅₀?=?750.0?±?1.5?µM) against yeast α-glucosidase with IC₅₀ values in the range of 74.0?±?0.7–298.3?±?0.9?µM. Kinetic study of the most potent compound 6v demonstrated that this compound is a competitive inhibitor for α-glucosidase (K_i value?=?75?µM). Furthermore, the in silico studies of the most potent compounds 6v and 6o confirmed that these compounds interacted with the key residues in the active site of α-glucosidase.     

Design,molecular docking and synthesis of novel 5,6-dichloro-2-methyl-1H-benzimidazole derivatives as potential urease enzyme inhibitors

A novel series of 5,6-dichloro-2-methyl-1H-benzimidazole derivatives was synthesized and then screened for their urease inhibitory activity. All compounds showed more potent inhibitory activity in the range of IC₅₀ = 0.0294 ± 0.0015–0.1494 ± 0.0041 µM than thiourea (IC₅₀ = 0.5117 ± 0.0159 µM), as a reference inhibitor. Among all the tested compounds, the compound 15 (IC₅₀ = 0.0294 ± 0.0015 µM) having strong electron-withdrawing nitro group on the phenyl ring was recorded as the most potent inhibitor of urease. All compounds were docked at the active sites of the Jack bean urease enzyme to investigate the reason of the inhibitory activity and the possible binding interactions of enzyme-ligand complexes.     

Benzylidine indane-1,3-diones: As novel urease inhibitors; synthesis,in vitro,and in silico studies

Current study deals with the evaluation of indane-1,3-dione based compounds as new class of urease inhibitors. For that purpose, benzylidine indane-1,3-diones (1–30) were synthesized and fully characterized by different spectroscopic techniques including EI-MS, HREI-MS, ¹H, and ¹³C NMR. All synthetic molecules 1–30 were evaluated for urease inhibitory activity and showed good to moderate inhibitory potential within the range of (IC₅₀ = 11.60 ± 0.3–257.05 ± 0.7 µM) as compared to the standard acetohydroxamic acid (IC₅₀ = 27.0 ± 0.5 µM). Compound 1 (IC₅₀ = 11.60 ± 0.3 µM) was found to be most potent inhibitor amongst all derivatives. The key binding interactions of most active compounds within the enzyme pocket were evaluated through in silico studies.     

Tyrosinase inhibitory effects of Vinca major and its secondary metabolites: Enzyme kinetics and in silico inhibition model of the metabolites validated by pharmacophore modelling

In the present study, we aimed to identify the tyrosinase enzyme inhibitory potential of Vinca major L. extract and its secondary metabolites. The extract possessed remarkable tyrosinase enzyme inhibitory effect with IC₅₀ value of 20.39 ± 0.44 µg/mL compared to the positive control, kojic acid (IC₅₀ 8.56 ± 0.17 µg/mL). Compounds 1 and 5 were the most potent isolates with IC₅₀ values of 32.41 ± 0.99 and 31.34 ± 0.75 µM, they were more potent than kojic acid (IC₅₀: 60.25 ± 0.54 µM). Compound 2 also exhibited remarkable tyrosinase inhibition with an IC₅₀ value of 64.51 ± 1.29 µM. An enzyme kinetics analysis revealed that 1 was a mixed-type, 2 and 5 were noncompetitive inhibitors. Using molecular docking, we predicted binding affinity and interactions of the compounds, which were in good alignment with a pharmacophore hypothesis generated out of a number of known tyrosinase inhibitors. The modelling studies underlined crucial interactions with the copper ions and residues around them such as Asn260, His263, and Met280.     

Synthesis and in vitro anticancer evaluation of some fused indazoles,quinazolines and quinolines as potential EGFR inhibitors

derivatives of benzo[g]indazole 5a, b, benzo[h]quinazoline 7, 12a-c, 13a-c and 15a-c and benzo[h]quinoline 17a-c and 19a-c were synthesized from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1). Anticancer activity of all the synthesized compounds was evaluated against four cancerous cell lines; HepG2, MCF-7, HCT116 and Caco-2. MCF-7 cells emerged as the most sensitive cell line against the target compounds. All the examined compounds, except 5a and 5b, displayed potent to moderate anticancer activity against MCF-7 cells with an IC₅₀ values ranging from 7.21 to 21.55 µM. In particular, compounds 15c and 19b emerged as the most potent derivatives against EGFR-expressing MCF-7 cells with IC₅₀ values = 7.70 ± 0.39 and 7.21 ± 0.43 μM, respectively. Additionally, both compounds did not display any significant cytotoxicity towards normal BHK-21 fibroblast cells (IC₅₀ value > 200 µM), thereby providing a good safety profile as anticancer agents. Furthermore, compounds 15c and 19b displayed potent inhibitory activity towards EGFR in the sub-micromolar range (IC₅₀ = 0.13 ± 0.01 and 0.14 ± 0.01 μM, respectively), compared to that of Erlotinib (IC₅₀ = 0.11 ± 0.01 μM). Docking studies for 15c and 19b into EGFR active site was carried out to explore their potential binding modes. Therefore, compounds 15c and 19b can be considered as interesting candidates for further development of more potent anticancer agents.     

Investigation of new quinoline derivatives as promising inhibitors of NTPDases: Synthesis,SAR analysis and molecular docking studies

Nucleoside triphosphate diphosphohydrolases (NTPDases), an important class of ectonucleotidases, are responsible for the sequential hydrolysis of extracellular nucleotides. However, over-expression of NTPDases has been linked with various pathological diseases e.g. cancer. Thus, to treat these diseases, the inhibitors of this class of enzyme are of interest. The significance of this class of enzyme encouraged us to synthesize a new class of quinoline derivatives with the aim to find selective and potent inhibitors of NTPDases. Therefore, a mild and efficient synthetic route was established for the synthesis of quinoline derivatives. The reaction was catalyzed by molecular iodine to afford the substituted quinoline derivatives. All the synthetic derivatives (3a-3w) were evaluated for their potential to inhibit the h-NTPDase1, 2, 3 and 8. Most of the compounds were identified as dual inhibitors of h-NTPDase1 and 8 with lower effects on h-NTPDase2 and 3. Two compounds i.e. 3f and 3t were identified as selective inhibitor of h-NTPDase1 whereas the compound 3s inhibited the h-NTPDase8 selectively. Moreover, the compounds 3p (IC₅₀ = 0.23 ± 0.01 µM), 3j (IC₅₀ = 21.0 ± 0.03 µM) 3d (IC₅₀ = 5.38 ± 0.21 µM) and 3c (IC₅₀ = 1.13 ± 0.04 µM) were found to be the most potent inhibitors of h-NTPDase1, 2, 3 and 8, respectively. To determine the binding interaction, molecular docking studies were also carried out.     

Synthesis, α-amylase inhibitory potential and molecular docking study of indole derivatives

In search of potent α-amylase inhibitor we have synthesized eighteen indole analogs (1–18), characterized by NMR and HR-EIMS and screened for α-amylase inhibitory activity. All analogs exhibited a variable degree of α-amylase inhibition with IC₅₀ values ranging between 2.031 ± 0.11 and 2.633 ± 0.05 μM when compared with standard acarbose having IC₅₀ values 1.927 ± 0.17 μM. All compounds showed good α-amylase inhibition. Compound 14 was found to be the most potent analog among the series. Structure-activity relationship has been established for all compounds mainly based on bringing about the difference of substituents on phenyl ring. To understand the binding interaction of the most active analogs molecular docking study was performed.     

Tyrosinase and α-glucosidase inhibitory potential of compounds isolated from Quercus coccifera bark: In vitro and in silico perspectives

Bark of Quercus coccifera is widely used in folk medicine. We tested tyrosinase and α-glucosidase inhibitory effects of Q. coccifera bark extract and isolated compounds from it. The extract inhibited tyrosinase with an IC₅₀ value of 75.13 ± 0.44 µg/mL. Among the isolated compounds, polydatin (6) showed potent tyrosinase inhibition compared to the positive control, kojic acid, with an IC₅₀ value of 4.05 ± 0.30 µg/mL. The Q. coccifera extract also inhibited α-glucosidase significantly with an IC₅₀ value of 3.26 ± 0.08 µg/mL. (-)-8-Chlorocatechin (5) was the most potent isolate, also more potent than the positive control, acarbose, with an IC₅₀ value of 43.60 ± 0.67 µg/mL. According to the kinetic analysis, 6 was a noncompetitive and 5 was a competitive inhibitor of tyrosinase, and 5 was a noncompetitive α-glucosidase inhibitor. In the light of these findings, we performed in silico molecular docking studies for 5 and 6 with QM/MM optimizations to predict their tyrosinase inhibition mechanisms at molecular level and search for correlations with the in vitro results. We found that the ionized form of 5 (5i) showed higher affinity and more stable binding to tyrosinase catalytic site than its neutral form, while 6 bound to the predicted allosteric sites of the enzyme better than the catalytic site.     

Exploring antidiabetic potential of adamantyl-thiosemicarbazones via aldose reductase (ALR2) inhibition

The role of aldose reductase (ALR2) in diabetes mellitus is well-established. Our interest in finding ALR2 inhibitors led us to explore the inhibitory potential of new thiosemicarbazones. In this study, we have synthesized adamantyl-thiosemicarbazones and screened them as aldehyde reductase (ALR1) and aldose reductase (ALR2) inhibitors. The compounds bearing phenyl 3a, 2-methylphenyl 3g and 2,6-dimethylphenyl 3m have been identified as most potent ALR2 inhibitors with IC₅₀ values of 3.99 ± 0.38, 3.55 ± 0.26 and 1.37 ± 0.92 µM, respectively, compared with sorbinil (IC₅₀ = 3.14 ± 0.02 μM). The compounds 3a, 3g, and 3m also inhibit ALR1 with IC₅₀ value of 7.75 ± 0.28, 7.26 ± 0.39 and 7.04 ± 2.23 µM, respectively. Molecular docking was also performed for putative binding of potent inhibitors with target enzyme ALR2. The most potent 2,6-dimethylphenyl bearing thiosemicarbazone 3m (IC₅₀ = 1.37 ± 0.92 µM for ALR2) and other two compound 3a and 3g could potentially lead for the development of new therapeutic agents.     

Synthesis and molecular docking study of some novel 2,3-disubstituted quinazolin-4(3H)-one derivatives as potent inhibitors of urease

A new series of 2,3-disubstituted quinazolin-4(3H)-one compounds including oxadiazole and furan rings was synthesized. Their inhibitory activities on urease were assessed in vitro. All newly synthesized compounds exhibited potent urease inhibitory activity in the range of IC₅₀ = 1.55 ± 0.07–2.65 ± 0.08 µg/mL, when compared with the standard urease inhibitors such as thiourea (IC₅₀ = 15.08 ± 0.71 µg/mL) and acetohydroxamic acid (IC₅₀ = 21.05 ± 0.96 µg/mL). 2,3-Disubstituted quinazolin-4(3H)-one derivatives containing furan ring (3a-e) were found to be the most active inhibitors when compared with the compounds 2a-e bearing oxadiazole ring. Compound 3a, bearing 4-chloro group on phenyl ring, was found as the most effective inhibitor of urease with the IC₅₀ value of 1.55 ± 0.11 µg/mL. The molecular docking studies of the newly synthesized compounds were performed to identify the probable binding modes in the active site of the Jack bean urease (JBU) enzymes.     

Probing the high potency of pyrazolyl pyrimidinetriones and thioxopyrimidinediones as selective and efficient non-nucleotide inhibitors of recombinant human ectonucleotidases

With the aim to discover novel, efficient and selective inhibitors of human alkaline phosphatase and nucleotide pyrophosphatase enzymes, two new series of pyrazolyl pyrimidinetriones (PPTs) (6a–g) and thioxopyrimidinediones (PTPs) (6h–n) were synthesized in good chemical yields using Knoevenagel condensation reaction between pyrazole carbaldehydes (4a–g) and pharmacologically active N-alkylated pyrimidinetrione (5a) and thioxopyrimidinedione (5b). The inhibition potential of the synthesized hybrid compounds was evaluated against human alkaline phosphatase (h-TNAP and h-IAP) and ectonucleotidase (h-NPP1 and h-NPP3) enzymes. Most of the tested analogs were highly potent with a variable degree of inhibition depending on the functionalized hybrid structure. The detailed structure-activity relationship (SAR) of PPT and PTP derivatives suggested that the compound with unsubstituted phenyl ring from PPT series led to selective and potent inhibition (6a; IC₅₀ = 0.33 ± 0.02 µM) of h-TNAP, whereas compound 6c selectively inhibited h-IAP isozyme with IC₅₀ value of 0.86 ± 0.04 µM. Similarly, compounds 6b and 6h were identified as the lead scaffolds against h-NPP1 and h-NPP3, respectively. The probable binding modes for the most potent inhibitors were elucidated through molecular docking analysis. Structure-activity relationships, mechanism of action, cytotoxic effects and druglikeness properties are also discussed.     

Design,synthesis, docking study, α-glucosidase inhibition,and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes

A novel series of acridine linked to thioacetamides 9a–o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC₅₀ = 80.0 ± 2.0–383.1 ± 2.0 µM against yeast α-glucosidase, when compared to the standard drug acarbose (IC₅₀ = 750.0 ± 1.5 µM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC₅₀ = 80.0 ± 2.0 μM). The in vitro cytotoxic assay of compounds 9a–o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a K_i of 85 μM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.     

Synthesis of novel quinoline-based thiadiazole,evaluation of their antileishmanial potential and molecular docking studies

New series of quinoline-based thiadiazole analogs (1–20) were synthesized, characterized by EI-MS, ¹H NMR and ¹³C NMR. All synthesized compounds were subjected to their antileishmanial potential. Sixteen analogs 1–10, 12, 13, 16, 17, 18 and 19 with IC₅₀ values in the range of 0.04 ± 0.01 to 5.60 ± 0.21 µM showed tremendously potent inhibition as compared to the standard pentamidine with IC₅₀ value 7.02 ± 0.09 µM. Analogs 11, 14, 15 and 20 with IC₅₀ 8.20 ± 0.35, 9.20 ± 0.40, 7.20 ± 0.20 and 9.60 ± 0.40 µM respectively showed good inhibition when compared with the standard. Structure-activity relationships have been also established for all compounds. Molecular docking studies were performed to determine the binding interaction of the compounds with the active site target.     

Design,synthesis, in vitro evaluation,molecular docking and ADME properties studies of hybrid bis-coumarin with thiadiazole as a new inhibitor of Urease

Hybrid bis-coumarin derivatives 1–18 were synthesized and evaluated for their in vitro urease inhibitory potential. All compounds showed outstanding urease inhibitory potential with IC₅₀ value (The half maximal inhibitory concentration) ranging in between 0.12 SD 0.01 and 38.04 SD 0.63 µM (SD standard deviation). When compared with the standard thiourea (IC₅₀ = 21.40 ± 0.21 µM). Among these derivatives, compounds 7 (IC₅₀ = 0.29 ± 0.01), 9 (IC₅₀ = 2.4 ± 0.05), 10 (IC₅₀ = 2.25 ± 0.05) and 16 (IC₅₀ = 0.12 ± 0.01) are better inhibitors of the urease compared with thiourea (IC₅₀ = 21.40 ± 0.21 µM). To find structure–activity relationship molecular docking as well as absorption, distribution, metabolism, and excretion (ADME) studies were also performed. Various spectroscopic techniques like ¹H NMR, ¹³C NMR, and EI-MS were used for characterization of all synthesized analogs. All compounds were tested for cytotoxicity and found non-toxic.     

Synthesis,biological evaluation,and molecular modelling of new naphthalene-chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting tubulin colchicine binding site

Abstract

A series of naphthalene-chalcone derivatives (3a–3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC₅₀ value of 1.42?±?0.15?µM, as compared to cisplatin (IC₅₀?=?15.24?±?1.27?µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G₂/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC₅₀ value of 8.4?µM, which was slightly more active than the reference compound colchicine (IC₅₀?=?10.6?µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.     

Synthesis, α-glucosidase inhibition and molecular docking study of coumarin based derivatives

We have synthesized seventeen Coumarin based derivatives (1–17), characterized by ¹HNMR, ¹³CNMR and EI-MS and evaluated for α-glucosidase inhibitory potential. Among the series, all derivatives exhibited outstanding α-glucosidase inhibition with IC₅₀ values ranging between 1.10 ± 0.01 and 36.46 ± 0.70 μM when compared with the standard inhibitor acarbose having IC₅₀ value 39.45 ± 0.10 μM. The most potent derivative among the series is derivative 3 having IC₅₀ value 1.10 ± 0.01 μM, which are many folds better than the standard acarbose. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituent’s on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.     

Design,synthesis, anticancer evaluation,molecular docking and cell cycle analysis of 3-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine derivatives as potent histone lysine demethylases (KDM) inhibitors and apoptosis inducers

A novel series of pyrazolo[1,5-a]pyrimidines were synthesized and proved by their spectral and elemental analysis, some elected of the newly synthesized compounds were examined for their cytotoxic activity employing MTT assay on two cancer cell lines (Breast and Hela cancers). Compounds 5, 7e and 7i showed the higher cytotoxicity against two cancer cell lines with (IC₅₀ = 13.91 ± 1.4 and 22.37 ± 1.8 μM/L), (IC₅₀ = 6.56 ± 0.5 and 8.72 ± 0.9 μM/L) and (IC₅₀ = 4.17 ± 0.2 and 5.57 ± 0.4 μM/L) for two cancer cell lines breast and hela respectively, using doxorubicin as a reference drug. The most potent cytotoxic active compounds 5, 7e and 7i presented inhibitory activity against KDM (histone lysine demethylases) with IC₅₀ = 4.05, 1.91 and 2.31 μM, respectively. The most potent KDM inhibitor 7e (IC₅₀ = 1.91 μM) showed to cause cell cycle arrest at G2/M phase by 4 folds than control and induce total apoptotic effect by 10 folds more than control. In silico studies performed on the more potent cytotoxic active compounds 5, 7e and 7i included lipinisk's rule of five. Moreover, molecular docking study was utilized to explore the binding mode of the most active compounds to the target enzyme (PDB-ID: 5IVE). Also, some bioinformatics studies were carried out for compounds 7e and 7i using Swiss ADME (Swiss Institute of bioinformatics 2018).     

Synthesis,and In Vitro and In Silico α-Glucosidase Inhibitory Studies of 5-Chloro-2-Aryl Benzo[d]thiazoles

Twenty-five derivatives of 5-chloro-2-aryl benzo[d]thiazole (1–25) were synthesized and evaluated for their α-glucosidase (S. cerevisiae EC 3.2.1.20) inhibitory activity in vitro. Among them eight compounds showed potent activity with IC₅₀ values between 22.1 ± 0.9 and 136.2 ± 5.7 μM, when compared with standard acarbose (IC₅₀ = 840 ± 1.73 μM). The most potent compounds 4, 9, and 10 showed IC₅₀ values in the range of 22.1 ± 0.9 to 25.6 ± 1.5 μM. Compounds 2, 5, 11, and 19 showed IC₅₀ values within the range of 40.2 ± 0.5 to 60.9 ± 2.0 μM. Compounds 1 and 3 were also found to be good inhibitors with IC₅₀ values 136.2 ± 5.7 and 104.8 ± 9.9 μM, respectively. Their activities were compared with α-glucosidase inhibitor drug acarbose (standard) (IC₅₀ = 840 ± 1.73 μM). The remaining compounds were inactive. Structure-activity relationships (SAR) have also been established. Kinetics studies indicated compounds 2, 3, 10, 19, and 25 to be non-competitive, while 1, 5, 9, and 11 as competitive inhibitors of α-glucosidase enzyme. All the active compounds (1–5, 9–11, and 19) were also found to be non-cytotoxic, in comparison to the standard drug i.e., doxorubicin (IC₅₀ = 0.80 ± 0.12 μM) in MTT assay. Furthermore, molecular interactions of active compounds with the enzyme binding sites were predicted through molecular modeling studies.     

Oxindole based oxadiazole hybrid analogs: Novel α-glucosidase inhibitors

Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. Beside these α-glucosidase inhibitors has been also used as anti-obesity and anti-viral drugs. Keeping in view the greater importance of α-glucosidase inhibitors here in this study we are presenting oxindole based oxadiazoles hybrid analogs (1–20) synthesis, characterized by different spectroscopic techniques including ¹H NMR and EI-MS and their α-glucosidase inhibitory activity. All compounds were found potent inhibitors for the enzyme with IC₅₀ values ranging between 1.25 ± 0.05 and 268.36 ± 4.22 µM when compared with the standard drug acarbose having IC₅₀ value 895.09 ± 2.04 µM. Our study identifies novel series of potent α-glucosidase inhibitors and further investigation on this may led to the lead compounds. A structure activity relationship has been established for all compounds. The interactions of the active compounds and enzyme active site were established with the help of molecular docking studies.