Rhodanine-benzamides as potential hits for α-amylase enzyme inhibitors and radical (DPPH and ABTS) scavengers.

A series of 3-substituted and 3,5-disubstituted rhodanine-based derivatives were synthesized from 3-aminorhodanine and examined for α-amylase inhibitory, DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activities in vitro. These derivatives displayed significant α-amylase inhibitory potential with IC50 values of 11.01-56.04 µM in comparison to standard acarbose (IC50 = 9.08 ± 0.07 µM). Especially, compounds 7 (IC50 = 11.01 ± 0.07 µM) and 8 (IC50 = 12.01 ± 0.07 µM) showed highest α-amylase inhibitory activities among the whole series. In addition to α-amylase inhibitory activity, all compounds also demonstrated significant scavenging activities against DPPH and ABTS radicals, with IC50 values ranging from 12.24 to 57.33 and 13.29-59.09 µM, respectively, as compared to the standard ascorbic acid (IC50 = 15.08 ± 0.03 µM for DPPH; IC50 = 16.09 ± 0.17 µM for ABTS). These findings reveal that the nature and position of the substituents on the phenyl ring(s) are crucial for variation in the activities. The structure-activity relationship (SAR) revealed that the compounds bearing an electron-withdrawing group (EWG) at para substitution possessed the highest activity. In kinetic studies, only the km value was changed, with no observed changes in Vmax, indicating a competitive inhibition. Molecular docking studies revealed important interactions between compounds and the α-amylase active pocket. Further advanced research needs to perform on the identified compounds in order to obtain potential antidiabetic agents.

Lactase can target cellular differentiation of Acanthamoeba castellanii belonging to the T4 genotype.

The free living Acanthamoeba spp. are ubiquitous amoebae associated with potentially blinding disease known as Acanthamoeba keratitis (AK) and a fatal central nervous system infection granulomatous amoebic encephalitis (GAE). With the inherent ability of cellular differentiation, it can phenotypically transform to a dormant cyst form from an active trophozoite form. Acanthamoeba cysts are highly resistant to therapeutic agents as well as contact lens cleaning solutions. One way to tackle drug resistance against Acanthamoeba is by inhibiting the formation of cysts from trophozoites. The biochemical analysis showed that the major component of Acanthamoeba cyst wall is composed of carbohydrate moieties such as galactose and glucose. The disaccharide of galactose and glucose is lactose. In this study, we analyzed the potential of lactase enzyme to target carbohydrate moieties of cyst walls. Amoebicidal assessment showed that lactase was ineffective against trophozoite of A. castellanii but enhanced amoebicidal effects of chlorhexidine. The lactase enzyme did not show any toxicity against normal human keratinocyte cells (HaCaT) at the tested range. Hence, lactase can be used for further assessment for development of potential therapeutic agents in the management of Acanthamoeba infection as well as formulation of effective contact lens disinfectants.

Effect of embelin on inhibition of cell growth and induction of apoptosis in Acanthamoeba castellanii.

Acanthamoeba castellanii is the causative agent of fatal encephalitis and blinding keratitis. Current therapies remain a challenge, hence there is a need to search for new therapeutics. Here, we tested embelin (EMB) and silver nanoparticles doped with embelin (EMB-AgNPs) against A. castellanii. Using amoebicidal assays, the results revealed that both compounds inhibited the viability of Acanthamoeba, having an IC50 of 27.16 ± 0.63 and 13.63 ± 1.08 µM, respectively, while causing minimal cytotoxicity against HaCaT cells in vitro. The findings suggest that both samples induced apoptosis through the mitochondria-mediated pathway. Differentially expressed genes analysis showed that 652 genes were uniquely expressed in treated versus untreated cells, out of which 191 were significantly regulated in the negative control vs. conjugate. Combining the analysis, seven genes (ARIH1, RAP1, H3, SDR16C5, GST, SRX1, and PFN) were highlighted as the most significant (Log2 (FC) value ± 4) for the molecular mode of action in vitro. The KEGG analysis linked most of the genes to apoptosis, the oxidative stress signaling pathway, cytochrome P450, Rap1, and the oxytocin signaling pathways. In summary, this study provides a thorough framework for developing therapeutic agents against microbial infections using EMB and EMB-AgNPs.

Alpha-Mangostin and its nano-conjugates induced programmed cell death in Acanthamoeba castellanii belonging to the T4 genotype.

Acanthamoeba are free living amoebae that are the causative agent of keratitis and granulomatous amoebic encephalitis. Alpha-Mangostin (AMS) is a significant xanthone; that demonstrates a wide range of biological activities. Here, the anti-amoebic activity of α-Mangostin and its silver nano conjugates (AMS-AgNPs) were evaluated against pathogenic A. castellanii trophozoites and cysts in vitro. Amoebicidal assays showed that both AMS and AMS-AgNPs inhibited the viability of A. castellanii dose-dependently, with an IC50 of 88.5 ± 2.04 and 20.2 ± 2.17 µM, respectively. Both formulations inhibited A. castellanii-mediated human keratinocyte cell cytopathogenicity. Functional assays showed that both samples caused apoptosis through the mitochondrial pathway and reduced mitochondrial membrane potential and ATP production, while increasing reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) cytochrome-c reductase in the cytosol. Whole transcriptome sequencing of A. castellanii showed the expression of 826 genes, with 447 genes being up-regulated and 379 genes being down-regulated post treatment. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the majority of genes were linked to apoptosis, autophagy, RAP1, AGE-RAGE and oxytocin signalling pathways. Seven genes (PTEN, H3, ARIH1, SDR16C5, PFN, glnA GLUL, and SRX1) were identified as the most significant (Log2 (FC) value 4) for molecular mode of action in vitro. Future in vivo studies with AMS and nanoconjugates are needed to realize the clinical potential of this work.

Syntheses, in vitro, and in silico studies of rhodanine-based schiff bases as potential α-amylase inhibitors and radicals (DPPH and ABTS) scavengers.

A two-step reaction method was used to synthesize a series of rhodanine-based Schiff bases (2-33) that were characterized using spectroscopic techniques. All compounds were assessed for α-amylase inhibitory and radical scavenging (DPPH and ABTS) activities. In comparison to the standard acarbose (IC50 = 9.08 ± 0.07 µM), all compounds demonstrated good to moderate α-amylase inhibitory activity (IC50 = 10.91 ± 0.08-61.89 ± 0.102 µM). Compounds also demonstrated significantly higher DPPH (IC50 = 10.33 ± 0.02-96.65 ± 0.03 µM) and ABTS (IC50 = 12.01 ± 0.12-97.47 ± 0.13 µM) radical scavenging activities than ascorbic acid (DPPH, IC50 = 15.08 ± 0.03 µM; ABTS, IC50 = 16.09 ± 0.17 µM). The limited structure-activity relationship (SAR) suggests that the position and nature of the substituted groups on the phenyl ring have a vital role in varying inhibitory potential. Among the series, compounds with an electron-withdrawing group at the para position showed the highest potency. Kinetic studies revealed that the compounds followed a competitive mode of inhibition. Molecular docking results are found to agree with experimental findings, showing that compounds reside in the active pocket due to the main rhodanine moiety.

Bioevaluation of synthetic pyridones as dual inhibitors of α-amylase and α-glucosidase enzymes and potential antioxidants.

Herein, a library of novel pyridone derivatives 1-34 was designed, synthesized, and evaluated for α-amylase and α-glucosidase inhibitory as well as antioxidant activities. Pyridone derivatives 1-34 were synthesized via a one-pot multi-component reaction of variously substituted aromatic aldehydes, acetophenone, ethyl cyanoacetate, and ammonium acetate in absolute ethanol. Synthetic compounds 1-34 were structurally characterized by different spectroscopic techniques. Most of the tested compounds showed more promising inhibition potential than the standard acarbose (IC50 = 14.87 ± 0.16 µM) but compounds 13 and 12 were found to be the most potent compounds with IC50 values of 9.20 ± 0.14 µM and 3.05 ± 0.18 µM against α-amylase and α-glucosidase enzymes, respectively. Compounds 1-34 also displayed moderate antioxidant potential in the range of IC50 = 96.50 ± 0.45 to 189.98 ± 1.00 µM in comparison to the control butylated hydroxytoluene (BHT) (IC50 = 66.50 ± 0.36 µM), in DPPH radical scavenging activities. Additionally, all synthetic derivatives were subjected to a molecular docking study to investigate the interaction details of compounds 1-34 (ligands) with the active site of enzymes (receptors). These results indicate that the newly synthesized pyridone class may serve as promising lead candidates for controlling diabetes mellitus and as antioxidants.

Indole Derivatives: Unveiling New Frontiers in Medicinal and Synthetic Organic Chemistry.

In recent years, significant attention has been given to indoles, a diverse group of heterocyclic compounds widely found in nature that play a crucial role in various bioactive natural and synthetic substances [...].

Synthesis, DFT Studies, Molecular Docking and Biological Activity Evaluation of Thiazole-Sulfonamide Derivatives as Potent Alzheimer's Inhibitors.

Alzheimer's disease is a major public brain condition that has resulted in many deaths, as revealed by the World Health Organization (WHO). Conventional Alzheimer's treatments such as chemotherapy, surgery, and radiotherapy are not very effective and are usually associated with several adverse effects. Therefore, it is necessary to find a new therapeutic approach that completely treats Alzheimer's disease without many side effects. In this research project, we report the synthesis and biological activities of some new thiazole-bearing sulfonamide analogs (1-21) as potent anti-Alzheimer's agents. Suitable characterization techniques were employed, and the density functional theory (DFT) computational approach, as well as in-silico molecular modeling, has been employed to assess the electronic properties and anti-Alzheimer's potency of the analogs. All analogs exhibited a varied degree of inhibitory potential, but analog 1 was found to have excellent potency (IC50 = 0.10 ± 0.05 µM for AChE) and (IC50 = 0.20 ± 0.050 µM for BuChE) as compared to the reference drug donepezil (IC50 = 2.16 ± 0.12 µM and 4.5 ± 0.11 µM). The structure-activity relationship was established, and it mainly depends upon the nature, position, number, and electron-donating/-withdrawing effects of the substituent/s on the phenyl rings.

New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family.

Chemo-resistant cancer cells acquire robust growth potential through cell signaling mechanisms such as the down-regulation of tumor suppressors and the up-regulation of pro-survival proteins, respectively. To overcome chemo-resistance of cancer, small molecule drugs that interact with the cell signaling proteins to enhance sensitization of cancer cells toward cancer therapies are likely to be effective for the treatment of chemo-drug resistant cancer. To identify high potency small molecules, a series of ten novel phenylquinazoline derivatives were synthesized to determine their cellular effects in MCF-7 and MCF-7- cisplatin-resistant (CR) human breast cancer cells which led to the identification of two bioactive compounds, SMS-IV-20 and SMS-IV-40, that exhibited an elevated level of cytotoxicity against the human breast cancer cells and spheroid cells. In addition, both compounds enhanced chemo-sensitization of the human breast cancer cells that were genetically engineered to express the tumor suppressor and pro-apoptotic proteins, MOAP-1, Bax, and RASSF1a (MBR), suggesting that the compounds interact with the MBR signaling pathway. Furthermore, when MCF-7-CR cells were treated with SMS-IV-20 and SMS-IV-40 in the presence of ABT-737, a BCL-XL and BCL-2 inhibitor, enhanced chemo-sensitization was observed, suggesting SMS-IV-20 and SMS-IV-40 exert antagonistic activity to regulate the functional activity of BCL-2 and BCL-XL. Western blot analysis showed that both SMS-IV-20 and SMS-IV-40 induced down-regulation of BCL-2 or both BCl-2 and BCL-XL expression, respectively while promoting the release of mitochondrial Cytochrome C. Taken together, the data showed that SMS-IV-20 and SMS-IV-40 are potent activators of apoptosis that enhance chemo-sensitization through their antagonistic actions on the pro-survival activity of the BCl-2 family in human cancer cells.

Dihydroquinazolin-4(1H)-one derivatives as novel and potential leads for diabetic management.

A variety of dihydroquinazolin-4(1H)-one derivatives (1-37) were synthesized via "one-pot" three-component reaction scheme by treating aniline and different aromatic aldehydes with isatoic anhydride in the presence of acetic acid. Chemical structures of compounds were deduced by different spectroscopic techniques including EI-MS, HREI-MS, 1H-, and 13C-NMR. Compounds were subjected to α-amylase and α-glucosidase inhibitory activities. A number of derivatives exhibited significant to moderate inhibition potential against α-amylase (IC50 = 23.33 ± 0.02-88.65 ± 0.23 µM) and α-glucosidase (IC50 = 25.01 ± 0.12-89.99 ± 0.09 µM) enzymes, respectively. Results were compared with the standard acarbose (IC50 = 17.08 ± 0.07 µM for α-amylase and IC50 = 17.67 ± 0.09 µM for α-glucosidase). Structure-activity relationship (SAR) was rationalized by analyzing the substituents effects on inhibitory potential. Kinetic studies were implemented to find the mode of inhibition by compounds which revealed competitive inhibition for α-amylase and non-competitive inhibition for α-glucosidase. However, in silico study identified several important binding interactions of ligands (synthetic analogues) with the active site of both enzymes.

Identification of Selective BRD9 Inhibitor via Integrated Computational Approach.

Bromodomain-containing protein 9 (BRD9), a member of the bromodomain and extra terminal domain (BET) protein family, works as an epigenetic reader. BRD9 has been considered an essential drug target for cancer, inflammatory diseases, and metabolic disorders. Due to its high similarity among other isoforms, no effective treatment of BRD9-associated disorders is available. For the first time, we performed a detailed comparative analysis among BRD9, BRD7, and BRD4. The results indicate that residues His42, Gly43, Ala46, Ala54, Val105, and Leu109 can confer the BRD9 isoform selectivity. The predicted crucial residues were further studied. The pharmacophore model's features were precisely mapped with some key residues including, Gly43, Phe44, Phe45, Asn100, and Tyr106, all of which play a crucial role in BRD9 inhibition. Docking-based virtual screening was utilized with the consideration of the conserved water network in the binding cavity to identify the potential inhibitors of BRD9. In this workflow, 714 compounds were shortlisted. To attain selectivity, 109 compounds were re-docked to BRD7 for negative selection. Finally, four compounds were selected for molecular dynamics studies. Our studies pave the way for the identification of new compounds and their role in causing noticeable, functional differences in isoforms and between orthologues.

Indole-Containing Natural Products 2019-2022: Isolations, Reappraisals, Syntheses, and Biological Activities.

Indole alkaloids represent a large subset of natural products, with more than 4100 known compounds. The majority of these alkaloids are biologically active, with some exhibiting excellent antitumor, antibacterial, antiviral, antifungal, and antiplasmodial activities. Consequently, the natural products of this class have attracted considerable attention as potential leads for novel therapeutics and are routinely isolated, characterized, and profiled to gauge their biological potential. However, data on indole alkaloids, their various structures, and bioactivities are complex due to their diverse sources, such as plants, fungi, bacteria, sponges, tunicates, and bryozoans; thus, isolation methods produce an incredible trove of information. The situation is exacerbated when synthetic derivatives, as well as their structures, bioactivities, and synthetic schemes, are considered. Thus, to make such data comprehensive and inform researchers about the current field's state, this review summarizes recent reports on novel indole alkaloids. It deals with the isolation and characterization of 250 novel indole alkaloids, a reappraisal of previously reported compounds, and total syntheses of indole alkaloids. In addition, several syntheses and semi-syntheses of indole-containing derivatives and their bioactivities are reported between January 2019 and July 2022.

Virtual Screening, Synthesis and Biological Evaluation of Streptococcus mutans Mediated Biofilm Inhibitors.

Dental caries, a global oral health concern, is a biofilm-mediated disease. Streptococcus mutans, the most prevalent oral microbiota, produces extracellular enzymes, including glycosyltransferases responsible for sucrose polymerization. In bacterial communities, the biofilm matrix confers resistance to host immune responses and antibiotics. Thus, in cases of chronic dental caries, inhibiting bacterial biofilm assembly should prevent demineralization of tooth enamel, thereby preventing tooth decay. A high throughput screening was performed in the present study to identify small molecule inhibitors of S. mutans glycosyltransferases. Multiple pharmacophore models were developed, validated with multiple datasets, and used for virtual screening against large chemical databases. Over 3000 drug-like hits were obtained that were analyzed to explore their binding mode. Finally, six compounds that showed good binding affinities were further analyzed for ADME (absorption, distribution, metabolism, and excretion) properties. The obtained in silico hits were evaluated for in vitro biofilm formation. The compounds displayed excellent antibiofilm activities with minimum inhibitory concentration (MIC) values of 15.26-250 µg/mL.

Synthesis of 2-Aminopyrimidine Derivatives and Their Evaluation as ß-Glucuronidase Inhibitors: In Vitro and In Silico Studies.

Currently the discovery and development of potent ß-glucuronidase inhibitors is an active area of research due to the observation that increased activity of this enzyme is associated with many pathological conditions, such as colon cancer, renal diseases, and infections of the urinary tract. In this study, twenty-seven 2-aminopyrimidine derivatives 1-27 were synthesized by fusion of 2-amino-4,6-dichloropyrimidine with a variety of amines in the presence of triethylamine without using any solvent and catalyst, in good to excellent yields. All synthesized compounds were characterized by EI-MS, HREI-MS and NMR spectroscopy. Compounds 1-27 were then evaluated for their ß-glucuronidase inhibitory activity, and among them, compound 24 (IC50 = 2.8 ± 0.10 µM) showed an activity much superior to standard D-saccharic acid 1,4-lactone (IC50 = 45.75 ± 2.16 µM). To predict the binding mode of the substrate and ß-glucuronidase, in silico study was performed. Conclusively, this study has identified a potent ß-glucuronidase inhibitor that deserves to be further studied for the development of pharmaceutical products.

Synthesis of New Triazole-Based Thiosemicarbazone Derivatives as Anti-Alzheimer's Disease Candidates: Evidence-Based In Vitro Study.

Triazole-based thiosemicarbazone derivatives (6a-u) were synthesized then characterized by spectroscopic techniques, such as 1HNMR and 13CNMR and HRMS (ESI). Newly synthesized derivatives were screened in vitro for inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives (except 6c and 6d, which were found to be completely inactive) demonstrated moderate to good inhibitory effects ranging from 0.10 ± 0.050 to 12.20 ± 0.30 µM (for AChE) and 0.20 ± 0.10 to 14.10 ± 0.40 µM (for BuChE). The analogue 6i (IC50 = 0.10 ± 0.050 for AChE and IC50 = 0.20 ± 0.050 µM for BuChE), which had di-substitutions (2-nitro, 3-hydroxy groups) at ring B and tri-substitutions (2-nitro, 4,5-dichloro groups) at ring C, and analogue 6b (IC50 = 0.20 ± 0.10 µM for AChE and IC50 = 0.30 ± 0.10 µM for BuChE), which had di-Cl at 4,5, -NO2 groups at 2-position of phenyl ring B and hydroxy group at ortho-position of phenyl ring C, emerged as the most potent inhibitors of both targeted enzymes (AChE and BuChE) among the current series. A structure-activity relationship (SAR) was developed based on nature, position, number, electron donating/withdrawing effects of substitution/s on phenyl rings. Molecular docking studies were used to describe binding interactions of the most active inhibitors with active sites of AChE and BuChE.

3-substituted coumarin derivatives over-activate the HslV protease: A potential drug target for antibacterial activity.

The bacterial HslVU complex consists of two different proteins, i.e., the HslV protease and the HslU ATPase. The functional HslVU enzyme complex forms only when the HslU c-terminal helix is inserted into the cavity located between two adjacent HslV monomers in order to allosterically activate the HslV protease. Based on its essential role in maintaining microbial proteostasis as well its absence from human beings, it is considered a promising therapeutic target for designing antibacterial agents. The goal of the present study was to find out potential drug candidates that could over-activate the HslV protease and produce aberrant proteolysis in pathogenic bacteria. Derivatives of 3-substituted coumarin have been identified as potential HslV protease activators based on their highest docking scores, ideal interaction patterns, and significant in-vitro HslV activation potential. Their ED50 values were in the sub-micromolar range, i.e., 0.4-0.48µM. The conformational stability of the contacts between the HslV dimer and the active compounds was further confirmed by molecular dynamics studies. Correspondingly, the ADMET characteristics of these lead molecules considerably demonstrated their significant non-toxic drug-like abilities. This research not only identified small non-peptidic HslV protease activators but also improved the understanding of the mode of action of 3-substituted coumarin derivatives as antibacterials.

Synthesis of azachalcones, their α-amylase, α-glucosidase inhibitory activities, kinetics, and molecular docking studies.

Diabetes being a chronic metabolic disorder have attracted the attention of medicinal chemists and biologists. The introduction of new and potential drug candidates for the cure and treatment of diabetes has become a major concern due to its increased prevelance worldwide. In the current study, twenty-seven azachalcone derivatives 3-29 were synthesized and evaluated for their antihyperglycemic activities by inhibiting α-amylase and α-glucosidase enzymes. Five compounds 3 (IC50 = 23.08 ± 0.03 µM), (IC50 = 26.08 ± 0.43 µM), 5 (IC50 = 24.57 ± 0.07 µM), (IC50 = 27.57 ± 0.07 µM), 6 (IC50 = 24.94 ± 0.12 µM), (IC50 = 27.13 ± 0.08 µM), 16 (IC50 = 27.57 ± 0.07 µM), (IC50 = 29.13 ± 0.18 µM), and 28 (IC50 = 26.94 ± 0.12 µM) (IC50 = 27.99 ± 0.09 µM) demonstrated good inhibitory activities against α-amylase and α-glucosidase enzymes, respectively. Acarbose was used as the standard in this study. Structure-activity relationship was established by considering the parent skeleton and different substitutions on aryl ring. The compounds were also subjected for kinetic studies to study their mechanism of action and they showed competitive mode of inhibition against both enzymes. The molecular docking studies have supported the results and showed that these compounds have been involved in various binding interactions within the active site of enzyme.

Synthesis of indole-based-thiadiazole derivatives as a potent inhibitor of α-glucosidase enzyme along with in silico study.

A series of nineteen (1-19) indole-based-thiadiazole derivatives were synthesized, characterized by 1HNMR, 13C NMR, MS, and screened for α-glucosidase inhibition. All analogs showed varied α-glucosidase inhibitory potential with IC50 value ranged between 0.95 ± 0.05 to 13.60 ± 0.30 µM, when compared with the standard acarbose (IC50 = 1.70 ± 0.10). Analogs 17, 2, 1, 9, 7, 3, 15, 10, 16, and 14 with IC50 values 0.95 ± 0.05, 1.10 ± 0.10, 1.30 ± 0.10, 1.60 ± 0.10, 2.30 ± 0.10, 2.30 ± 0.10, 2.80 ± 0.10, 4.10 ± 0.20 and 4.80 ± 0.20 µM respectively showed highest α-glucosidase inhibition. All other analogs also exhibit excellent inhibitory potential. Structure activity relationships have been established for all compounds primarily based on substitution pattern on the phenyl ring. Through molecular docking study, binding interactions of the most active compounds were confirmed. We further studied the kinetics study of analogs 1, 2, 9 and 17 and found that they are Non-competitive inhibitors.

Synthesis, in vitro antiurease, in vivo antinematodal activity of quinoline analogs and their in-silico study.

Synthesis of quinoline analogs and their urease inhibitory activities with reference to the standard drug, thiourea (IC50 = 21.86 ± 0.40 µM) are presented in this study. The inhibitory activity range is (IC50 = 0.60 ± 0.01 to 24.10 ± 0.70 µM) which displayed that it is most potent class of urease inhibitor. Analog 1-9, and 11-13 emerged with many times greater antiurease potential than thiourea, in which analog 1, 2, 3, 4, 8, 9, and 11 (IC50 = 3.50 ± 0.10, 7.20 ± 0.20, 1.30 ± 0.10, 2.30 ± 0.10, 0.60 ± 0.01, 1.05 ± 0.10 and 2.60 ± 0.10 µM respectively) were appeared the most potent ones among the series. In this context, most potent analogs such as 1, 3, 4, 8, and 9 were further subjected for their in vitro antinematodal study against C. elegans to examine its cytotoxicity under positive control of standard drug, Levamisole. Consequently, the cytotoxicity profile displayed that analogs 3, 8, and 9 were found with minimum cytotoxic outline at higher concentration (500 µg/mL). All analogs were characterized through 1H NMR, 13C NMR and HR-EIMS. The protein-ligand binding interaction for most potent analogs was confirmed via molecular docking study.

Biology-oriented drug synthesis (BIODS), in vitro urease inhibitory activity, and in silico studies on ibuprofen derivatives.

Novel ibuprofen derivatives 1-19 including ibuprofen hydrazide 1, and substituted thiourea derivatives 2-19 were synthesized and characterized by EI-MS, FAB-MS, HREI-MS, HRFAB-MS, 1H-, and 13C-NMR spectroscopic techniques. The synthetic molecules 1-19 were examined for their in vitro urease inhibition and were found to display a diversified degree of inhibitory potential in the range of IC50 = 2.96-178 µM as compared to the standard thiourea (IC50 = 21.32 ± 0.22 µM). Out of nineteen, thirteen derivatives 2-4, 6, 7, 9, 11-15, 17, and 18 demonstrated remarkable inhibitory activity with IC50 values of 2.96 ± 1.11 to 16.1 ± 1.07 µM, compound 5 exhibited moderate inhibition with IC50 value of 37.3 ± 0.41 µM, whereas, compounds 1, 8, and 10 demonstrated weak inhibition against urease enzyme. Almost all structural features are participating in the activity; however, limited structure-activity relationship was discussed on the basis of different structural features, i.e., different functional groups and their positions at aryl part. In addition, molecular docking study was performed in order to understand the ligands binding interactions with the active site of urease enzyme.