Design and discovery of anthranilamide derivatives as a potential treatment for neurodegenerative disorders via targeting cholinesterases and monoamine oxidases.

Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC50 values of 0.12 ± 0.01 and 0.49 ± 0.02 µM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC50 value of 0.44 ± 0.02 µM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC50 value of 0.06 ± 0.01 µM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.

Urease inhibitory potential of pyridine-containing triazolothiadiazole and triazolothiadiazine scaffolds for the treatment of ulceration and kidney stone: in vitro screening, kinetics mechanism, and in silico computational analysis.

The hyperactivity of urease enzyme leads to various complications including gastritis and peptic ulcer. A diverse variety of natural and synthetic inhibitors have shown a tremendous potential to inhibit the urease enzyme, thus decreasing the hyperactivity and reducing the risk for the development of urinary calculi and other similar problems. Therefore, we herein report a family of fused heterocycles such as triazolothiadiazoles (4a-h, 5a-f) and triazolothiadiazines (6a-h) as potential antiurease agents with IC50 values in the range 10.41-41.20 µM. Several compounds were identified as potential lead candidates. Among them, compounds 4e and 4f from triazolothiadiazole series showed the highest inhibitory potential with IC50 values of 11.62 ± 0.34 and 10.35 ± 0.14 µM), respectively, whereas 6e from triazolothiadiazine series emerged as the most potent inhibitor with an IC50 value of 10.41 ± 0.13 µM. These compounds exhibited two-fold strong inhibitory efficacy against urease as compared to standard inhibitor, thiourea (IC50 = 22.48 ± 0.67 µM). The mechanistic insights from kinetics experiments for compounds 4e, 4f, and 6e revealed the competitive mode of inhibition with Ki values of 8.65 ± 0.004, 7.04 ± 0.012, and 8.31 ± 0.007 µM, respectively. The in vitro results were further explored through in silico computational docking analysis which reflects that binding of ligands with Ni ions and His492 play a crucial role in urease inhibition. In silico predicted physicochemical properties and ADME profile reflect drug-like nature of these molecules.Communicated by Ramaswamy H. Sarma.

Triazolothiadiazoles and Triazolothiadiazines as New and Potent Urease Inhibitors: Insights from In Vitro Assay, Kinetics Data, and In Silico Assessment.

Hyperactivity of the urease enzyme induces the pathogenesis of peptic ulcers and gastritis. The identification of new urease inhibitors can reduce the activity of urease. Therefore, in the current study, we have evaluated 28 analogues of triazolothiadiazole and triazolothiadiazine heteroaromatics for their in vitro urease inhibitory efficacy. All the tested compounds displayed a remarkable inhibitory potential ranging from 3.33 to 46.83 µM. Among them, compounds 5k and 5e emerged as lead inhibitors with IC50 values of 3.33 ± 0.11 and 3.51 ± 0.49 µM, respectively. The potent inhibitory potential of these compounds was ∼6.5-fold higher than that of the marketed drug thiourea (IC50 = 22.45 ± 0.30 µM). The mechanistic insights from kinetics experiments of the highest potent inhibitors (4g, 5e, and 5k) revealed a competitive type of inhibition with ki values 2.25 ± 0.0028, 3.11 ± 0.0031, and 3.62 ± 0.0034 µM, respectively. In silico modeling was performed to investigate the binding interactions of potent inhibitors with the enzyme active site residues, which strongly supported our experimental results. Furthermore, ADME analysis also showed good druglikeness properties demonstrating the potential of these compounds to be developed as lead antiurease agents.

Triazolothiadiazoles and triazolothiadiazines as potent α-glucosidase inhibitors: Mechanistic insights from kinetics studies, molecular docking and dynamics simulations.

Diabetes mellitus has been considered as a serious health problem worldwide due its high prevalence rate and associated complications. In this context, the current research work aims at exploring new structural leads for the treatment of a major metabolic disorder, diabetes mellitus type 2. The outcomes of our prior studies on a diverse set of triazolothiadiazole and triazolothiadiazine derivatives and their therapeutic potential, encouraged us to explore their anti-diabetic competency by targeting the key carbohydrate catabolic enzyme, α-glucosidase. Therefore, all these analogues were examined to reveal their contribution towards this severe metabolic issue. Interestingly, all the tested compounds (2a-2l and 3a-3p) exhibited several times more potent α-glucosidase inhibitory activities (IC50 in the range of 2.44-219.93 µM) as compared to marketed drug, acarbose (IC50 = 873.34 ± 1.67 µM). Furthermore, their mechanism of action was investigated through in vitro kinetics studies which revealed compounds 3a, 3d, 3o, and 2k as competitive inhibitors, and 3f as a mixed type inhibitor of α-glucosidase. In addition, in silico molecular docking and molecular dynamics simulations were applied to observe the mode of interaction of the active hits within the binding pocket of α-glucosidase. Both docking and simulation results favored our in vitro mechanistic analysis.

Ultrathin Graphene Oxide-Based Nanocomposite Membranes for Water Purification.

Two-dimensional graphene oxide (GO)-based lamellar membranes have been widely developed for desalination, water purification, gas separation, and pervaporation. However, membranes with a well-organized multilayer structure and controlled pore size remain a challenge. Herein, an easy and efficient method is used to fabricate MoO2@GO and WO3@GO nanocomposite membranes with controlled structure and interlayer spacing. Such membranes show good separation for salt and heavy metal ions due to the intensive stacking interaction and electrostatic attraction. The as-prepared composite membranes showed high rejection rates (˃70%) toward small metal ions such as sodium (Na+) and magnesium (Mg2+) ions. In addition, both membranes also showed high rejection rates ˃99% for nickel (Ni2+) and lead (Pb2+) ions with good water permeability of 275 ± 10 L m-2 h-1 bar-1. We believe that our fabricated membranes will have a bright future in next generation desalination and water purification membranes.

Inhibitory Efficacy of Thiosemicarbazones for Carbonic Anhydrase II (Bovine and Human) as a Target of Calcification and Tumorigenicity.

BACKGROUND: Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. OBJECTIVE: In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized. METHODS: This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out. RESULTS: In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety plays a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetic studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki). CONCLUSION: Subsequently, (3e, 3f, 3l and 3p) were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 µM, while (3d) as a noncompetitive inhibitor of bCA-II (Ki = 2.5 ± 0.015 µM), however, (3g) demonstrated competitive inhibition of hCA-II with a Ki value of 5.95 ± 0.002 µM. The selectivity index reflects that compound (3g) is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.

Preparation of mixed-mode stationary phase for separation of peptides and proteins in high performance liquid chromatography.

Porous silica particles were prepared by sol-gel method with some modification to get wide-pore particles. These particles were derivatized with N-phenylmaleimide-methylvinylisocyanate (PMI) and styrene by reversible addition fragmentation chain transfer (RAFT) polymerization to prepare N-phenylmaleimide embedded polystyrene (PMP) stationary phases. Narrow bore stainless steel column (100 × 1.8 mm i.d) was packed by slurry packing method. The chromatographic performance of PMP column was evaluated for the separation of synthetic peptides mixture composed of five peptides (Gly-Tyr, Gly-Leu-Tyr, Gly-Gly-Tyr-Arg, Tyr-Ile-Gly-Ser-Arg, Leucine enkephalin) and tryptic digest of human serum albumin (HAS) respectively. Number of theoretical plates as high as 280,000 plates/m were obtained for peptides mixture at optimum elution condition. Separation performance of the developed column was compared with commercial Ascentis Express RP-Amide column and it was observed that separation performance of PMP column was better than commercial column in terms of separation efficiency and resolution.

Facile synthesis of Zn-doped CdS nanowires with efficient photocatalytic performance.

In this study, one-dimensional zinc (Zn)-doped cadmium sulphide (CdS) nanowires were synthesised by a solvothermal method. The Zn doping concentrations were varied from 1 to 5 mol% (ZnxCd1-xS where x = 0.001, 0.003 and 0.005). As-prepared materials were characterised by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray (EDX) spectroscopy and UV-visible spectroscopy. Electrochemical impedance spectroscopy (EIS) was conducted to measure the charge transfer resistance. The photocatalytic performance of prepared materials was evaluated by the photodegradation of methylene blue (MB) dye. The result showed that 5% Zn-doped CdS is more photoactive as compared to other corresponding doped and undoped CdS. The increase in photocatalytic performance is due to improvement in the charge separation.

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer's Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 µM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 µM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer's disease.

Antiproliferative and Pro-Apoptotic Effects of Thiazolo[3,2-b][1,2,4]triazoles in Breast and Cervical Cancer Cells.

BACKGROUND AND OBJECTIVES: Cancer is one of the leading causes of death in the world affecting millions of people. The commercially available anticancer drugs lack the selectivity and show several undue side effects during the biologically targeted therapy, thus calling for the exploration of wider chemical space to furnish new structural leads with promising anticancer potential. In this endeavor, we synthesized a series of coumarinyl thiazolotriazoles with diverse functional group tolerance and will be tested for their anticancer properties against cancer cell lines (HeLa and MCF-7) and a normal cell line (BHK-21). MATERIALS AND METHODS: To overcome such complications, in the current study, we evaluated the cytotoxic effects of coumarinyl thiazolotriazole hybrids on human breast adenocarcinoma (MCF-7), cervical adenocarcinoma (HeLa) cells and normal cells i.e., Baby Hamster Kidney cells (BHK-21) using MTT (dimethyl-2-thiazolyl- 2,5-diphenyl-2H-tetrazolium bromide) assay. DNA binding studies of compound 6c was performed on Herring- Sperm DNA (HS-DNA) and docking studies were also carried out. The mechanistic studies were performed on potent compounds by fluorescent microscopic studies, release of Lactate Dehydrogenase (LDH) and mitochondrial membrane potential, activation of caspase-9 and -3 and flow cytometric analysis. RESULTS: As revealed by MTT assay, compounds 6m and 6c were identified as the most potent derivatives among the tested series with IC50 values of 5.64 and 29.1 µM against HeLa and MCF cells, respectively as compared to cisplatin which gave IC50 values of 11.3 and 6.20 µM, respectively. DNA binding studies of compound 6c showed the binding of compound in DNA with Gibbs free energy of ‒17 KJ/mol and docking studies validated the DNA binding studies. Fluorescent microscopic studies using 4',6-diamidino-2-phenylindole (DAPI) and Propidium Iodide (PI) staining confirmed the occurrence of apoptosis in HeLa cells treated with the most active compound 6m. Moreover, compounds 6m and 6c also triggered the release of Lactate Dehydrogenase (LDH) in treated HeLa and MCF-7 cells while a luminescence assay displayed a remarkable increase in the activity of caspase-9 and -3. Moreover, flow cytometric results revealed that compound 6m caused G0 /G1 arrest in the treated HeLa cells. CONCLUSION: Our results suggested that the compound possesses chemotherapeutic properties against breast cancer and cervical adenocarcinoma cells, thus warranting further research to test the anticancer efficacy of this compound at clinical level.

Alkynoates as Versatile and Powerful Chemical Tools for the Rapid Assembly of Diverse Heterocycles under Transition-Metal Catalysis: Recent Developments and Challenges.

Heterocycles, heteroaromatics and spirocyclic entities are ubiquitous components of a wide plethora of synthetic drugs, biologically active natural products, marketed pharmaceuticals and agrochemical targets. Recognizing their high proportion in drugs and rich pharmacological potential, these invaluable structural motifs have garnered significant interest, thus enabling the development of efficient catalytic methodologies providing access to architecturally complex and diverse molecules with high atom-economy and low cost. These chemical processes not only allow the formation of diverse heterocycles but also utilize a range of flexible and easily accessible building units in a single operation to discover diversity-oriented synthetic approaches. Alkynoates are significantly important, diverse and powerful building blocks in organic chemistry due to their unique and inherent properties such as the electronic bias on carbon-carbon triple bonds posed by electron-withdrawing groups or the metallic coordination site provided by carbonyl groups. The present review highlights the comprehensive picture of the utility of alkynoates (2007-2019) for the synthesis of various heterocycles (> 50 types) using transition-metal catalysts (Ru, Rh, Pd, Ir, Ag, Au, Pt, Cu, Mn, Fe) in various forms. The valuable function of versatile alkynoates (bearing multifunctional groups) as simple and useful starting materials is explored, thus cyclizing with an array of coupling partners to deliver a broad range of oxygen-, nitrogen-, sulfur-containing heterocycles alongside fused-, and spiro-heterocyclic compounds. In addition, these examples will also focus the scope and reaction limitations, as well as mechanistic investigations into the synthesis of these heterocycles. The biological significance will also be discussed, citing relevant examples of drug molecules highlighting each class of heterocycles. This review summarizes the recent developments in the synthetic methods for the synthesis of various heterocycles using alkynoates as readily available starting materials under transition-metal catalysis.

Utilization of the common functional groups in bioactive molecules: Exploring dual inhibitory potential and computational analysis of keto esters against α-glucosidase and carbonic anhydrase-II enzymes.

Diabetes mellitus, a progressive chronic disease, characterized by the abnormal carbohydrate metabolism is associated with severe health complications including long term dysfunction or failure of several organs, cardiovascular and micro-angiopathic problems (neuropathy, nephropathy, retinopathy). Despite the existence of diverse chemical structural libraries of α-glucosidase inhibitors, the limited diabetic treatment due to the adverse side effects such as abdominal distention, flatulence, diarrhoea, and liver damage associated with these inhibitors encourage the medicinal research community to design and develop new and potent inhibitors of α-glucosidase with better pharmacokinetic properties. In this perspective, we demonstrate the successful integration of common functional groups (ketone & ester) in one combined pharmacophore which is favorable for the formation of hydrogen bonds and other weaker interactions with the target proteins. These keto ester derivatives were screened for their α-glucosidase inhibition potential and the in vitro results revealed compound 3c as the highly active inhibitor with an IC50 value of 12.4 ± 0.16 µM compared to acarbose (IC50 = 942 ± 0.74 µM). This inhibition potency was ~76-fold higher than acarbose. Other potent compounds were 3f (IC50 = 28.0 ± 0.28 µM), 3h (IC50 = 33.9 ± 0.09 µM), 3g (IC50 = 34.1 ± 0.04 µM), and 3d (IC50 = 76.5 ± 2.0 µM). In addition, the emerging use of carbonic anhydrase inhibitors for the treatment of diabetic retinopathy (a leading cause of vision loss) prompted us to screen the keto ester derivatives for the inhibition of carbonic anhydrase-II. Compound 3b was found significantly active against carbonic anhydrase-II with an IC50 of 16.5 ± 0.92 µM (acetazolamide; IC50 = 18.2 ± 1.23 µM). Compound 3a also exhibited comparable potency with an IC50 value of 18.9 ± 1.08 µM. Several structure-activity relationship analyses depicted the influence of the substitution pattern on both the aromatic rings. Molecular docking analysis revealed the formation of several H-bonding interactions through the ester carbonyl and the nitro oxygens of 3c with the side chains of His348, Arg212 and His279 in the active pocket of α-glucosidase whereas 3b interacted with His95, -OH of Thr197, Thr198 and WAT462 in the active site of carbonic anhydrase-II. Furthermore, evaluation of ADME properties suggests the safer pharmacological profile of the tested derivatives.

New Hybrid Scaffolds Based on Carbazole-Chalcones as Potent Anticancer Agents.

BACKGROUND AND OBJECTIVES: Despite various technological advances for the treatment of cancer, the identification of new chemical entities with potent anticancer effects remain an indispensable requirement of the time due to multi-drug resistance exhibited by previously developed anticancer drugs. Particularly, the hybrid drugs incorporating two individual bioactive pharmacophores present medicinally important structural leads, thus improving the pharmacodynamic profile of the drug molecules. The antiproliferative and pro-apoptotic activity of the carbazole-chalcone hybrids on human breast and cervical cancer cells will be examined. MATERIALS AND METHODS: To overcome such complications, in the current study, we evaluated the cytotoxic effects of carbazole-chalcone hybrids on human breast adenocarcinoma (MCF-7), cervical adenocarcinoma (HeLa) cells and normal cells, i.e., Baby Hamster Kidney cells (BHK-21) using MTT (dimethyl-2-thiazolyl-2,5- diphenyl-2H-tetrazolium bromide) assay. The mechanistic studies were performed on potent compound 4g by fluorescent microscopic studies, release of Lactate Dehydrogenase (LDH) and mitochondrial membrane potential, activation of caspase-9 and -3 and flow cytometric analysis. RESULTS: As revealed by MTT assay, compound 4g was identified as the most potent derivative among the tested series with IC50 values of 5.64 and 29.15µM against HeLa and MCF-7 cells, respectively. The results were compared with cisplatin. Fluorescent microscopic studies using 4',6-diamidino-2-phenylindole (DAPI) and Propidium Iodide (PI) staining confirmed the occurrence of apoptosis in HeLa cells treated with the most active compound 4g. Moreover, compound 4g also triggered the release of Lactate Dehydrogenase (LDH) in treated HeLa and MCF-7 cells while a fluorescence assay displayed a remarkable increase in the activity of caspase-9 and -3. Moreover, flow cytometric results revealed that compound 4g caused G0/G1 arrest in the treated HeLa cells. CONCLUSION: Our results demonstrated that the compound 4g possesses chemotherapeutic properties against breast cancer and cervical adenocarcinoma cells, thus warranting further research to test the anticancer potential of this compound at preclinical and clinical level.

Robust therapeutic potential of carbazole-triazine hybrids as a new class of urease inhibitors: A distinctive combination of nitrogen-containing heterocycles.

The inhibition of urease enzyme is very important as it plays a key role in the treatment of several urinary and gastrointestinal tract infections. This enzyme provides a suitable environment for Helicobacter pylori at the low pH of the stomach, a causative agent of gastric and peptic ulcer that may lead to cancer. In agriculture, the high urease content causes environmental and economic problems. In this pursuit, given the well-established importance of integrated pharmacophores in medicinal chemistry and to explore new inhibitors of urease featuring two distinct heterocyclic functionalities, we herein report a facile synthesis of carbazole-triazine hybrids (3a-j). These new propeller-shaped chemical scaffolds were evaluated for their urease inhibitory potential in order to identify suitable leads. The initial structure-activity survey work guided through in vitro bioactivity results recognized 3e and 3f as new starting point hits incorporating bulky iodo (3e) and strong electron-withdrawing nitro (3f) groups at the para-position of aryl amine component. The potent compounds (3e &3f) exhibited the highest activity with IC50 values of 5.6 and 6.7 µM, respectively. In the molecular docking analysis, these compounds depicted excellent binding interactions with the active site residues. The key interactions observed include hydrogen bonding, π-π interactions, π-cation and nickel atom coordination to the triazine nitrogen of both inhibitors.

Exploring biological efficacy of coumarin clubbed thiazolo[3,2-b][1,2,4]triazoles as efficient inhibitors of urease: A biochemical and in silico approach.

Combating several pathological conditions associated with ureolytic enzyme (urease) remains a formidable challenge because of the lack of effective and safe drug therapies. In this regard, the development of potent inhibitors of urease could be considered as a promising remedy. Herein, we report a new library of structurally diverse hybrid heteroaromatics featuring coumarin and thiazolotriazole motifs in one combined unit. These new chemical scaffolds accessed through the integration approach were shown to inhibit the enzyme urease from jack bean at variable efficacies. An initial structure-activity relationship analysis guided through the variation of several functional groups at the aryl ring connected to the thiazole core revealed compound 6o (IC50 = 4.35 ±â€¯0.18 µM) as the most potent inhibitor. The inhibitory strength of 6o was 5-fold compared to thiourea (standard; IC50 = 20.8 ±â€¯0.59 µM). In the molecular docking analysis, 6o was stabilized in the active pocket through various binding interactions. The presence of an amino moiety at the meta position of the phenyl ring facilitates hydrogen bonding with the sulfhydryl group of Cys322 (2.11 Å) in addition to an interaction observed between the thiazole sulfur and nickel atoms present in the active site. Moreover, this amino group also interacts with the carbonyl oxygen of Ala366 at a distance of 2.75 Å. The chromenone moiety of compound 6o is stabilized by the side chains of various amino acid residues including Ala279, Thr301, Pro303, Thr304, His315 and Met367.

Developing new hybrid scaffold for urease inhibition based on carbazole-chalcone conjugates: Synthesis, assessment of therapeutic potential and computational docking analysis.

Although a diverse range of chemical entities offering striking therapeutic potential against urease enzyme has been reported, the key challenges (toxicity and safety) associated with these inhibitors create a large unmet medical need to unveil new, potent and safe inhibitors of urease enzyme. In this pursuit, the present study demonstrates the successful synthesis of carbazole-chalcone hybrids (4a-n) in good yields. The evaluation of the preliminary in vitro biological results showed that selected members of the investigated library of hybrid compounds possess excellent urease inhibitory efficacy. In particular, compounds 4c and 4k were the most potent inhibitors with lowest IC50 values of 8.93 ±â€¯0.21 and 6.88 ±â€¯0.42 µM, respectively. Molecular docking analysis of the most potent inhibitor 4k suggests that the compound is fitted neatly at the active site interface and mediates interaction with both nickel atoms present in the active site. Several other obvious interactions including metal-carbonyl contact, hydrogen bonding and hydrophobic interactions were also observed, playing a crucial part in the stabilization of 4k in the active site of urease.

Developing hybrid molecule therapeutics for diverse enzyme inhibitory action: Active role of coumarin-based structural leads in drug discovery.

Hybrid drugs featuring two or more potentially bioactive pharmacophores have been recognized as advanced and superior chemical entities to simultaneously modulate multiple drug targets of multifactorial diseases, thus overcoming the severe side effects associated with a single drug molecule. The selection of these chemical moieties to produce hybrid structures with druggable properties is generally facilitated by the observed and/or anticipated synergistic pharmacological activities of the individual molecules. In this perspective, coumarin template has extensively been studied in pursuit of structurally diverse leads for drug development due to high affinity and specificity to different molecular targets. This review highlights the most commonly exploited approaches conceptualizing the design and construction of hybrid molecules by coupling two or more individual fragments with or without an appropriate linker. In addition to the design strategies, this review also summarizes and reflects on the therapeutic potential of these hybrid molecules for diverse enzyme inhibitory action as well as their observed structure-activity relationship (SAR). Several key features of the synthesized hybrid structures that assert a profound impact on the inhibitory function have also been discussed alongside computational investigations, inhibitor molecular diversity and selectivity toward multiple drug targets. Finally, these drug discovery and development efforts should serve as a handy reference aiming to provide a useful platform for the exploration of new coumarin-based compounds with enhanced enzyme inhibitory profile.

Combined in Vitro and in Silico Studies for the Anticholinesterase Activity and Pharmacokinetics of Coumarinyl Thiazoles and Oxadiazoles.

In a continuation of our previous work for the exploration of novel enzyme inhibitors, two new coumarin-thiazole 6(a-o) and coumarin-oxadiazole 11(a-h) hybrids have been designed and synthesized. All the compounds were characterized by 1H- and 13C-NMR spectroscopy and elemental analysis. New hybrid analogs were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in order to know their potential for the prevention of Alzheimer's disease (AD). In coumarinyl thiazole series, compound 6b was found as the most active member against AChE having IC50 value of 0.87 ± 0.09 µM, while the compound 6j revealed the same efficacy against BuChE with an IC50 value of 11.01 ± 3.37 µM. In case of coumarinyl oxadiazole series, 11a was turned out to be the lead candidate against AChE with an IC50 value of 6.07 ± 0.23 µM, whereas compound 11e was found significantly active against BuChE with an IC50 value of 0.15 ± 0.09 µM. To realize the binding interaction of these compounds with AChE and BuChE, the molecular docking studies were performed. Compounds from coumarinyl thiazole series with potent AChE activity (6b, 6h, 6i, and 6k) were found to interact with AChE in the active site with MOE score of -10.19, -9.97, -9.68, and -11.03 Kcal.mol-1, respectively. The major interactions include hydrogen bonding, π-π stacking with aromatic residues, and interaction through water bridging. The docking studies of coumarinyl oxadiazole derivatives 11(a-h) suggested that the compounds with high anti-butyrylcholinesterase activity (11e, 11a, and 11b) provided MOE score of -9.9, -7.4, and -8.2 Kcal.mol-1, respectively, with the active site of BuChE building π-π stacking with Trp82 and water bridged interaction.

A new entry into the portfolio of α-glucosidase inhibitors as potent therapeutics for type 2 diabetes: Design, bioevaluation and one-pot multi-component synthesis of diamine-bridged coumarinyl oxadiazole conjugates.

Diabetes mellitus (DM), a chronic multifarious metabolic disorder resulting from impaired glucose homeostasis has become one of the most challenging diseases with severe life threat to public health. The inhibition of α-glucosidase, a key carbohydrate hydrolyzing enzyme, could serve as one of the effective methodology in both preventing and treating diabetes through controlling the postprandial glucose levels and suppressing postprandial hyperglycemia. In this context, three series of diamine-bridged bis-coumarinyl oxadiazole conjugates were designed and synthesized by one-pot multi-component methodology. The synthesized conjugates (4a-j, 5a-j, 6a-j) were evaluated as potential inhibitors of glucosidases. Compound 6f containing 4,4'-oxydianiline linker was identified as the lead and selective inhibitor of α-glucosidase enzyme with an IC50 value of 0.07 ±â€¯0.001 µM (acarbose: IC50 = 38.2 ±â€¯0.12 µM). This inhibition efficacy was ∼545-fold higher compared to the standard drug. Compound 6f was also emerged as the lead molecule against intestinal maltase-glucoamylase with good inhibition strength (IC50 = 0.04 ±â€¯0.02 µM) compared to acarbose (IC50 = 0.06 ±â€¯0.01 µM). Against ß-glucosidase enzyme, compound 6 g was noted as the lead inhibitor with IC50 value of 0.08 ±â€¯0.002 µM. Michaelis-Menten kinetic experiments were performed to explore the mechanism of inhibition. Molecular docking studies of the synthesized library of hybrid structures against glucosidase enzyme were performed to describe ligand-protein interactions at molecular level that provided an insight into the biological properties of the analyzed compounds. The results suggested that the inhibitors could be stabilized in the active site through the formation of multiple interactions with catalytic residues in a cooperative fashion. In addition, strong binding interactions of the compounds with the amino acid residues were effective for the successful identification of α-glucosidase inhibitors.

Quinolinic Carboxylic Acid Derivatives as Potential Multi-target Compounds for Neurodegeneration: Monoamine Oxidase and Cholinesterase Inhibition.

BACKGROUND: Parkinson's disease (PD), a debilitating and progressive disorder, is among the most challenging and devastating neurodegenerative diseases predominantly affecting the people over 60 years of age. OBJECTIVES: To confront PD, an advanced and operational strategy is to design single chemical functionality able to control more than one target instantaneously. METHODS: In this endeavor, for the exploration of new and efficient inhibitors of Parkinson's disease, we synthesized a series of quinoline carboxylic acids (3a-j) and evaluated their in vitro monoamine oxidase and cholinesterase inhibitory activities. The molecular docking and in silico studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. Moreover, molecular properties were calculated to evaluate the druglikeness of the compounds. RESULTS: The biological evaluation results revealed that the tested compounds were highly potent against monoamine oxidase (A & B), 3c targeted both the isoforms of MAO with IC50 values of 0.51 ± 0.12 and 0.51 ± 0.03 µM, respectively. The tested compounds also demonstrated high and completely selective inhibitory action against acetylcholinesterase (AChE) with IC50 values ranging from 4.36 to 89.24 µM. Among the examined derivatives, 3i was recognized as the most potent inhibitor of AChE with an IC50 value of 4.36 ± 0.12 ±µM. CONCLUSION: The compounds appear to be promising inhibitors and could be used for the future development of drugs targeting neurodegenerative disorders.