Synthesis and biological evaluation of novel N-arylidenequinoline-3-carbohydrazides as potent β-glucuronidase inhibitors

Thirty N-arylidenequinoline-3-carbohydrazides (1–30) have been synthesized and evaluated against β-glucuronidase inhibitory potential. Twenty four analogs showed outstanding β-glucuronidase activity having IC₅₀ values ranging between 2.11 ± 0.05 and 46.14 ± 0.95 than standard d-saccharic acid 1,4 lactone (IC₅₀ = 48.4 ± 1.25 μM). Six analogs showed good β-glucuronidase activity having IC₅₀ values ranging between 49.38 ± 0.90 and 80.10 ± 1.80. Structure activity relationship and the interaction of the active compounds and enzyme active site with the help of docking studies were established. Our study identifies novel series of potent β-glucuronidase inhibitors for further investigation.     

Synthesis of indole analogs as potent β-glucuronidase inhibitors

Natural products are the main source of motivation to design and synthesize new molecules for drug development. Designing new molecules against β-glucuronidase inhibitory is utmost essential. In this study indole analogs (1–35) were synthesized, characterized using various spectroscopic techniques including ¹H NMR and EI-MS and evaluated for their β-glucuronidase inhibitory activity. Most compounds were identified as potent inhibitors for the enzyme with IC₅₀ values ranging between 0.50 and 53.40 μM, with reference to standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Structure-activity relationship had been also established. The results obtained from docking studies for the most active compound 10 showed that hydrogen bond donor features as well as hydrogen bonding with (Oε1) of nucleophilic residue Glu540 is believed to be the most importance interaction in the inhibition activity. It was also observed that hydroxyl at fourth position of benzylidene ring acts as a hydrogen bond donor and interacts with hydroxyl (OH) on the side chain of catalysis residue Tyr508. The enzyme-ligand complexed were being stabilized through electrostatic π-anion interaction with acid-base catalyst Glu451 (3.96 Å) and thus preventing Glu451 from functioning as proton donor residue.     

Synthesis of oxadiazole-coupled-thiadiazole derivatives as a potent β-glucuronidase inhibitors and their molecular docking study

A new series of oxadiazole with thiadiazole moiety (6–27) were synthesized, characterized by different spectroscopic techniques and evaluated for β-glucuronidase inhibitory potential. Sixteen analogs such as 6, 7, 8, 9, 10, 12, 13, 14, 17, 18, 20, 23, 24, 25, 26 and 27 showed IC₅₀ values in the range of 0.96 ± 0.01 to 46.46 ± 1.10 μM, and hence were found to have excellent inhibitory potential in comparison to standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Two analogs such as 16 and 19 showed moderate inhibitory potential while analogs 11, 15, 21 and 22 were found inactive. Our study identifies new series of potent β-glucuronidase inhibitors for further investigation. Structure activity relationships were established for all compounds which showed that the activity is varied due to different substituents on benzene ring. The interaction of the compounds with enzyme active site were confirmed with the help of docking studies, which reveals that the electron withdrawing group and hydroxy group make the molecules more favorable for enzyme inhibition.     

Evaluation of bisindole as potent β-glucuronidase inhibitors: Synthesis and in silico based studies

Bisindole analogs 1–17 were synthesized and evaluated for their in vitro β-glucuronidase inhibitory potential. Out of seventeen compounds, the analog 1 (IC₅₀ = 1.62 ± 0.04 μM), 6 (IC₅₀ = 1.86 ± 0.05 μM), 10 (IC₅₀ = 2.80 ± 0.29 μM), 9 (IC₅₀ = 3.10 ± 0.28 μM), 14 (IC₅₀ = 4.30 ± 0.08 μM), 2 (IC₅₀ = 18.40 ± 0.09 μM), 19 (IC₅₀ = 19.90 ± 1.05 μM), 4 (IC₅₀ = 20.90 ± 0.62 μM), 7 (IC₅₀ = 21.50 ± 0.77 μM), and 3 (IC₅₀ = 22.30 ± 0.02 μM) showed superior β-glucuronidase inhibitory activity than the standard (d-saccharic acid 1,4-lactone, IC₅₀ = 48.40 ± 1.25 μM). In addition, molecular docking studies were performed to investigate the binding interactions of bisindole derivatives with the enzyme. This study has identified a new class of potent β-glucouronidase inhibitors.     

Synthesis, β-glucuronidase inhibition and molecular docking studies of hybrid bisindole-thiosemicarbazides analogs

Hybrid bisindole-thiosemicarbazides analogs (1–18) were synthesized and screened for β-glucuronidase activity. All compounds showed varied degree of β-glucuronidase inhibitory potential when compared with standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Compounds 4, 7, 9, 6, 5, 12, 17 and 18 showed exceptional β-glucuronidase inhibition with IC₅₀ values ranging from 0.1 to 5.7 μM. Compounds 1, 3, 8, 16, 13, 2 and 14 also showed better activities than standard with IC₅₀ values ranging from 7.12 to 15.0 μM. The remaining compounds 10, 11, and 15 showed good inhibitory potential with IC₅₀ values 33.2 ± 0.75, 21.4 ± 0.30 and 28.12 ± 0.25 μM respectively. Molecular docking studies were carried out to confirm the binding interaction of the compounds.     

Synthesis of novel β-carbolines with efficient DNA-binding capacity and potent cytotoxicity

A series of water-soluble β-carbolines, bearing a flexible amino side chain, was prepared and evaluated in vitro against a panel of human tumor cell lines. The N⁹-arylated alkyl substituted β-carbolines represented the most interesting cytotoxic activities, and compound 7b was found to be the most potent antitumor agent with IC₅₀ values lower than 10 μM against eight human tumor cell lines. The results confirmed that the N⁹-arylated alkyl substituents of β-carboline nucleus played an important role in the modulation of the cytotoxic potencies. In addition, these compounds were found to exhibit significant DNA-binding affinity.     

Potential repurposing of known drugs as potent bacterial β-glucuronidase inhibitors

The active metabolite of the chemotherapeutic irinotecan, SN-38, is detoxified through glucuronidation and then excreted into the gastrointestinal tract. Intestinal bacteria convert the glucuronidated metabolite back to the toxic SN-38 using β-glucuronidase (GUS), resulting in debilitating diarrhea. Inhibiting GUS activity may relieve this side effect of irinotecan. In this study, we sought to determine whether any known drugs have GUS inhibitory activity. We screened a library of Food and Drug Administration-approved drugs with a cell-free biochemical enzyme assay using purified bacterial GUS. After triage, five drugs were confirmed to inhibit purified bacterial GUS. Three of these were the monoamine oxidase inhibitors nialamide, isocarboxazid, and phenelzine with average IC(50) values for inhibiting GUS of 71, 128, and 2300 nM, respectively. The tricyclic antidepressant amoxapine (IC(50) = 388 nM) and the antimalarial mefloquine (IC(50) = 1.2 μM) also had activity. Nialamide, isocarboxazid, and amoxapine had no significant activity against purified mammalian GUS but showed potent activity for inhibiting endogenous GUS activity in a cell-based assay using living intact Escherichia coli with average IC(50) values of 17, 336, and 119 nM, respectively. Thus, nialamide, isocarboxazid, and amoxapine have potential to be repurposed as therapeutics to reduce diarrhea associated with irinotecan chemotherapy and warrant further investigation for this use.     

Synthesis of benzothiazole derivatives as a potent α-glucosidase inhibitor

Diabetes is one of the pre-dominant metabolic disorders all over the world. It is the prime reason of mortality and morbidity due to hyperglycemia which is link with numerus obstacles. Delaying absorption and digestion of carbohydrate has great therapeutic impact for governing postprandial hyperglycemia. Consequently, alpha glucosidase is one of the potential therapeutic approaches that reduce absorption of glucose and delay carbohydrate digestion hence maintaining blood glucose level. In this regard we have synthesized benzothiazole based oxadiazole in search of potent anti-diabetic agent as α-glucosidase Inhibitors. Benzothiazole based oxadiazole derivatives 1–23 have been synthesized, characterized by ¹HNMR, ¹³CNMR, and MS and evaluated for α-glucosidase Inhibition. All analogs exhibited a varying degree of α-glucosidase inhibitory activity with IC₅₀ values ranging in between 0.5 ± 0.01–30.90 ± 0.70 μM when compared with the standard acarbose (IC₅₀ = 866.30 ± 3.20 μM). Structure activity relationship has been established for all compounds. Molecular docking studies were performed to predict the binding interaction of the compounds with the active site of enzyme.     

Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective β3-adrenergic receptor agonists

In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human β3-, β2-, and β1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the β3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective β3-AR agonist, with an EC₅₀ value of 0.28 μM and no agonistic activity for either the β1- or β2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.     

One-pot synthesis of thioxo-tetrahydropyrimidine derivatives as potent β-glucuronidase inhibitor,biological evaluation,molecular docking and molecular dynamics studies

A series of N,N-diethyl phenyl thioxo-tetrahydropyrimidine carboxamide have been synthesized and investigated for their β-glucuronidase inhibitory activities. All molecules exhibited excellent inhibition with IC₅₀ values ranging from 0.35 to 42.05 µM and found to be even more potent than the standard d-saccharic acid. Structure-activity relationship analysis indicated that the meta-aryl-substituted derivatives significantly influenced β-glucuronidase inhibitory activities while the para-substitution counterpart outperforming moderate potency. The most potent compound in this series was 4g bearing thiophene motif with IC₅₀ of 0.35 ± 0.09 µM. To verify the SAR, molecular docking and molecular dynamics studies were also performed.     

Synthesis of novel pyrazole–thiadiazole hybrid as potential potent and selective cyclooxygenase-2 (COX-2) inhibitors

A series of 1,3,4-trisubstituted pyrazole derivatives (3a–f), (4a–f), and (5a–f) have been synthesized and evaluated for their cyclooxygenase (COX-1 and COX-2) inhibitory activity. The structures of newly synthesized compounds were characterized by IR, ¹H NMR, and mass spectral analysis. All of the compounds showed good inhibition of COX-2 with IC₅₀ of 1.33–17.5 μM. Among these derivatives, compound (5c) was the most potent and selective COX-2 inhibitor (IC₅₀ = 1.33 μM), with a significant selectivity index (SI >60). Molecular docking studies were carried out in order to predict the hypothetical binding mode of these compounds to the COX-2 isoenzyme. The result of present study suggests that pyrazole–thiadiazole hybrid could be an interesting approach for the design of new selective COX-2 inhibitory agents.     

2,5-Disubstituted thiadiazoles as potent β-glucuronidase inhibitors; Synthesis,in vitro and in silico studies

Twenty-five thiadiazole derivatives 1–25 were synthesized from methyl 4-methoxybenzoate via hydrazide and thio-hydrazide intermediates, and evaluated for their potential against β-glucuronidase enzyme. Most of the compounds including 1 (IC₅₀ = 26.05 ± 0.60 μM), 2 (IC₅₀ = 42.53 ± 0.80 μM), 4 (IC₅₀ = 38.74 ± 0.70 μM), 5 (IC₅₀ = 9.30 ± 0.29 μM), 6 (IC₅₀ = 6.74 ± 0.26 μM), 7 (IC₅₀ = 18.40 ± 0.66 μM), and 15 (IC₅₀ = 18.10 ± 0.53 μM) exhibited superior activity potential than the standard d-saccharic acid-1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interaction with enzyme active site.     

Discovery of a novel hybrid from finasteride and epristeride as 5α-reductase inhibitor

Finasteride and epristeride both inhibit 5α-reductase with high potency via competitive and non-competitive mechanism, respectively. A new hybrid of finasteride and epristeride was designed as a new 5α-reductase inhibitor based on combination principles in medicinal chemistry. Human 5β-reductase was chosen as a plausible surrogate of 5α-reductase type II and the results indicate that although the hybrid compound possesses the main bulk of epristeride, its inhibitory mechanism is same as of finasteride. The hybrid turned out to be a potent 5α-reductase inhibitor in low IC₅₀ ranges.     

Synthesis of β-ionone derived chalcones as potent antimicrobial agents

A series of chalcones (3a–v) have been synthesized by condensation of β-ionone (1) with a variety of aldehydes (2a–v). The synthesized compounds have been screened for their in vitro antimicrobial activity against five bacterial and five fungal strains, using disc diffusion assay. The evaluated compounds display a wide range of activities, from completely inactive to the highly active compounds. Some of the compounds are also active against methicillin resistant staphylococcus aureus (MRSA).     

Synthesis and biological activities of novel indole derivatives as potent and selective PPARγ modulators

Starting from the structure of Telmisartan, a new series of potent and selective PPARγ modulators was identified. The synthesis, in vitro and in vivo evaluation of the most potent compounds are reported and the X-ray structure of compound 7b bound to the PPARγ ligand binding domain is described.     

Synthesis and SAR of novel benzoxaboroles as a new class of β-lactamase inhibitors

A new class of benzoxaborole β-lactamase inhibitors were designed and synthesized. 6-Aryloxy benzoxaborole 22 inhibited AmpC P99 and CMY-2 with K_i values in the low nanomolar range. Compound 22 restored antibacterial activity of ceftazidime against Enterobacter cloacae P99 expressing AmpC, a class C β-lactamase enzyme. The SAR around the arylbenzoxaboroles, which included the influence of linker and substitutions was also established.     

Synthesis,molecular docking studies of hybrid benzimidazole as α-glucosidase inhibitor

Thiourea derivatives having benzimidazole 1–17 have been synthesized, characterized by ¹H NMR, ¹³C NMR and EI-MS and evaluated for α-glucosidase inhibition. Identification of potential α-glucosidase inhibitors were done by in vitro screening of 17 thiourea bearing benzimidazole derivatives using Baker’s yeast α-glucosidase enzyme. Compounds 1–17 exhibited a varying degree of α-glucosidase inhibitory activity with IC₅₀ values between 35.83 ± 0.66 and 297.99 ± 1.20 μM which are more better than the standard acarbose (IC₅₀ = 774.5 ± 1.94 μM). Compound 10 and 14 showed significant inhibitory effects with IC₅₀ value 50.57 ± 0.81 and 35.83 ± 0.66 μM, respectively better than the rest of the series. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction of the compounds.     

Synthesis and structure–activity relationship of dicationic diaryl ethers as novel potent anti-MRSA and anti-VRE agents

A series of dicationic diaryl ethers have been synthesized and evaluated for in vitro antibacterial activities, including drug resistant bacterial strains. Most of these compounds have shown potent antibacterial activities. Several compounds, such as piperidinyl and thiomorpholinyl compounds 9e and 9l, improved the antimicrobial selectivity and kept potent anti-MRSA and anti-VRE activity. The most potent bis-indole diphenyl ether 19 exhibited anti-MRSA MIC value of ?0.06 μg/mL and enhanced antimicrobial selectivity.     

Synthesis and structure–activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents

This study describes the synthesis and structure–activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect.     

Synthesis and optimization of novel 4,4-disubstituted cyclohexylbenzamide derivatives as potent 11β-HSD1 inhibitors

The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.