Evaluation of synthetic aminoquinoline derivatives as urease inhibitors: in vitro, in silico and kinetic studies.

Background: Quinoline and acyl thiourea scaffolds have major chemical significance in medicinal chemistry. Quinoline-based acyl thiourea derivatives may potentially target the urease enzyme. Materials & methods: Quinoline-based acyl thiourea derivatives 1-26 were synthesized and tested for urease inhibitory activity. Results: 19 derivatives (1-19) showed enhanced urease enzyme inhibitory potential (IC50 = 1.19-18.92 µM) compared with standard thiourea (IC50 = 19.53 ± 0.032 µM), whereas compounds 20-26 were inactive. Compounds with OCH3, OC2H5, Br and CH3 on the aryl ring showed significantly greater inhibitory potential than compounds with hydrocarbon chains of varying length. Molecular docking studies were conducted to investigate ligand interactions with the enzyme's active site. Conclusion: The identified hits can serve as potential leads against the drug target urease in advanced studies.

2-Oxoquinoline-based-thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors.

Alzheimer's disease (AD) presents a multifactorial neurological disorder with multiple enzyme involvement in its onset. Conventional monotherapies fall short in providing long-term relief, necessitating the exploration of alternative multitargeting approaches to address the complexity of AD. Therefore, the design, synthesis, and in vitro and in silico evaluation of 2-oxoquinoline-based thiosemicarbazones 9a-r as multipotent analogs, able to simultaneously inhibit the cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of AD, are reported. In the in vitro experimental evaluation of MAO and ChE inhibition, all tested compounds demonstrated remarkable potency exhibiting nonselective inhibition of both MAO-A and MAO-B, and selective inhibition of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE), with 9d, 9j, and 9m evolving as lead compounds for MAO-A, MAO-B, and AChE, displaying IC50 values of 0.35 ± 0.92, 0.50 ± 0.02, and 0.25 ± 0.13 µM, respectively. Moreover, the kinetic studies revealed that all tested compounds inhibited all three enzymes through a competitive mode of inhibition. Furthermore, the molecular docking studies of the most active compounds revealed several crucial interactions, particularly hydrogen bonding interactions. These interactions were observed between the nitrogen and sulfur atoms of thiosemicarbazone and the nitrogen and oxygen atoms of the quinoline ring with various amino acids, suggesting the strong interactions of these compounds with the enzymes.

Therapeutic potential of 1,3,4-oxadiazoles as potential lead compounds for the treatment of Alzheimer's disease.

Monoamine oxidase and cholinesterase enzymes are important targets for the treatment of several neurological diseases especially depression, Parkinson disease and Alzheimer's. Here, we report the synthesis and testing of new 1,3,4-oxadiazole derivatives as novel inhibitors of monoamine oxidase enzymes (MAO-A and MAO-B) and cholinesterase enzymes (acetyl and butyryl cholinesterase (AChE, BChE). Compounds 4c, 4d, 4e, 4g, 4j, 4k, 4m, 4n displayed promising inhibitory effects on MAO-A (IC50: 0.11-3.46 µM), MAO-B (IC50: 0.80-3.08 µM) and AChE (IC50: 0.83-2.67 µM). Interestingly, compounds 4d, 4e and 4g are multitargeting MAO-A/B and AChE inhibitors. Also, Compound 4m displayed promising MAO-A inhibition with IC50 of 0.11 µM and high selectivity (∼25-fold) over MAO-B and AChE enzymes. These newly synthesized analogues represent promising hits for the development of promising lead compounds for neurological disease treatment.

Synthesis and Evaluation of Amide and Thiourea Derivatives as Carbonic Anhydrase (CA) Inhibitors.

Series of sulfonamide-substituted amide (9-11), benzamide (12-15), and 1,3-disubstituted thiourea (17-26) derivatives were synthesized from a common precursor, i.e., substituted benzoyl chlorides. Structures of all of the synthesized compounds were characterized by spectroscopic techniques (1H nuclear magnetic resonance (NMR),13C NMR, and Fourier transform infrared spectroscopy (FTIR)). All of the amide (9-15) and thiourea (17-26) derivatives were screened against human carbonic anhydrases, hCA-II, hCA IX, and hCA-XII. Sulfonamide-substituted amides 9, 11, and 12 were found to be excellent selective inhibitors with IC50 values of 0.18 ± 0.05, 0.17 ± 0.05, and 0.58 ± 0.05 µM against hCA II, hCA IX, and hCA XII, respectively. Compound 9 was found to be highly selective for hCA II and about 6-fold more potent as compared to the standard antagonist, acetazolamide. Safe toxicity profiling of the most potent and selective compounds was determined against normal BHK-21 and HEK-293 T cells. Molecular docking studies were performed, which described the type of interactions between the synthesized compounds and enzyme proteins. In addition, in silico absorption, distribution, metabolism, and excretion (ADME) studies were performed, which showed that all of the synthesized molecules fulfilled the druggability criteria.

Exploring Novel Pyridine Carboxamide Derivatives as Urease Inhibitors: Synthesis, Molecular Docking, Kinetic Studies and ADME Profile.

The rapid development of resistance by ureolytic bacteria which are involved in various life-threatening conditions such as gastric and duodenal cancer has induced the need to develop a new line of therapy which has anti-urease activity. A series of pyridine carboxamide and carbothioamide derivatives which also have some novel structures were synthesized via condensation reaction and investigated against urease for their inhibitory action. Among the series, 5-chloropyridine-2 yl-methylene hydrazine carbothioamide (Rx-6) and pyridine 2-yl-methylene hydrazine carboxamide (Rx-7) IC50 = 1.07 ± 0.043 µM, 2.18 ± 0.058 µM both possessed significant activity. Furthermore, molecular docking and kinetic studies were performed for the most potent inhibitors to demonstrate the binding mode of the active pyridine carbothioamide with the enzyme urease and its mode of interaction. The ADME profile also showed that all the synthesized molecules present oral bioavailability and high GI absorption.

Development, Molecular Docking, and In Silico ADME Evaluation of Selective ALR2 Inhibitors for the Treatment of Diabetic Complications via Suppression of the Polyol Pathway.

Diabetic complications are associated with overexpression of aldose reductase, an enzyme that catalyzes the first step of the polyol pathway. Osmotic stress in the hyperglycemic state is linked with the intracellular accumulation of sorbitol along with the depletion of NADPH and eventually leads to oxidative stress via formation of reactive oxygen species and advanced glycation end products (AGEs). These kinds of mechanisms cause the development of various diabetic complications including neuropathy, nephropathy, retinopathy, and atherosclerotic plaque formation. Various aldose reductase inhibitors have been developed to date for the treatment of diabetic complications, but all have failed in different stages of clinical trials due to toxicity and poor pharmacokinetic profiles. This toxicity is rooted in a nonselective inhibition of both ALR2 and ALR1, homologous enzymes involved in the metabolism of toxic aldehydes such as methylglyoxal and 3-oxyglucosazone. In the present study, we developed a series of thiosemicarbazone derivatives as selective inhibitors of ALR2 with both antioxidant and antiglycation potential. Among the synthesized compounds, 3c exhibited strong and selective inhibition of ALR2 (IC50 1.42 µM) along with good antioxidant and antiglycative properties. The binding mode of 3c was assessed through molecular docking and cluster analysis via MD simulations, while in silico ADME evaluation studies predicted the compounds' druglike properties. Therefore, we report 3c as a drug candidate with promising antioxidant and antiglycative properties that may be useful for the treatment of diabetic complications through selective inhibition of ALR2.

Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study.

The role of aldose reductase (ALR2) in causing diabetic complications is well-studied, with overactivity of ALR2 in the hyperglycemic state leading to an accumulation of intracellular sorbitol, depletion of cytoplasmic NADPH and oxidative stress and causing a variety of different conditions including retinopathy, nephropathy, neuropathy and cardiovascular disorders. While previous efforts have sought to develop inhibitors of this enzyme in order to combat diabetic complications, non-selective inhibition of both ALR2 and the homologous enzyme aldehyde reductase (ALR1) has led to poor toxicity profiles, with no drugs targeting ALR2 currently approved for therapeutic use in the Western world. In the current study, we have synthesized a series of N-substituted thiosemicarbazones with added phenolic moieties, of which compound 3m displayed strong and selective ALR2 inhibitory activity in vitro (IC50 1.18 µM) as well as promising antioxidant activity (75.95% free radical scavenging activity). The target binding modes of 3m were studied via molecular docking studies and stable interactions with ALR2 were inferred through molecular dynamics simulations. We thus report the N-substituted thiosemicarbazones as promising drug candidates for selective inhibition of ALR2 and possible treatment of diabetic complications.

Development of coumarin-thiosemicarbazone hybrids as aldose reductase inhibitors: Biological assays, molecular docking, simulation studies and ADME evaluation.

The over expression of aldose reductase (ALR2) in the state of hyperglycemia causes the conversion of glucose into sorbitol and initiates polyol pathway. Accumulation of sorbitol in insulin insensitive tissue like peripheral nerves, glomerulus and eyes, induces diabetic complications like neuropathy, nephropathy and retinopathy. For the treatment of diabetic complications, the inhibition of aldose reductase (ALR2) is a promising approach. A series of coumarin-based thiosemicarbazone derivatives was synthesized as potential inhibitor of aldose reductase. Compound N-(2-fluorophenyl)-2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)hydrazinecarbiothioamide (3n) was found to be the most promising inhibitor of ALR2 with an IC50 in micromolar range (2.07 µM) and high selectivity, relative to ALR1. The crystal structure of ALR2 complexed with 3n explored the types of interaction pattern which further demonstrated its high affinity. Compound 3n has excellent lead-likeness, underlined by its physicochemical parameters, and can be considered as a likely prospect for further structural optimization to get a drugable molecule.

Synthesis of indole-substituted thiosemicarbazones as an aldose reductase inhibitor: an in vitro, selectivity and in silico study.

Aim: Indole is an important component of many drug molecules, and its conjugation with thiosemicarbazone moiety would be advantageous in finding lead compounds for the development of diabetic complications. Methodology: We have designed, synthesized and evaluated a series of 17 indole-thiosemicarbazones (3a-q) as aldose reductase (ALR2) and aldehyde reductase (ALR1) inhibitors. Results: After in vitro evaluation, all indole-thiosemicarbazones showed significant inhibition against both enzyme ALR1 and ALR2 with IC50 in range of 0.42-20.7 and 1.02-19.1 µM, respectively. The docking study was also carried out to consider the putative binding of molecules with the target enzymes. Conclusion: Compound 3f was found to be most active and selective for ALR2. The indole-thiosemicarbazones series described here has selective hits for diabetes-mellitus-associated complications.

Rhodanine-3-acetamide derivatives as aldose and aldehyde reductase inhibitors to treat diabetic complications: synthesis, biological evaluation, molecular docking and simulation studies.

In diabetes, increased accumulation of sorbitol has been associated with diabetic complications through polyol pathway. Aldose reductase (AR) is one of the key factors involved in reduction of glucose to sorbitol, thereby its inhibition is important for the management of diabetic complications. In the present study, a series of seven 4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetamide derivatives 3(a-g) were synthesized by the reaction of 5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2a) and 5-(4-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2b) with different amines. The synthesized compounds 3(a-g) were investigated for their in vitro aldehyde reductase (ALR1) and aldose reductase (ALR2) enzyme inhibitory potential. Compound 3c, 3d, 3e, and 3f showed ALR1 inhibition at lower micromolar concentration whereas all the compounds were more active than the standard inhibitor valproic acid. Most of the compounds were active against ALR2 but compound 3a and 3f showed higher inhibition than the standard drug sulindac. Overall, the most potent compound against aldose reductase was 3f with an inhibitory concentration of 0.12 ± 0.01 µM. In vitro results showed that vanillin derivatives exhibited better activity against both aldehyde reductase and aldose reductase. The molecular docking studies were carried out to investigate the binding affinities of synthesized derivatives with both ALR1 and ALR2. The binding site analysis of potent compounds revealed similar interactions as were found by cognate ligands within the active sites of enzymes.

Exploring synthetic and therapeutic prospects of new thiazoline derivatives as aldose reductase (ALR2) inhibitors.

Inhibition of aldose reductase (ALR2) by using small heterocyclic compounds provides a viable approach for the development of new antidiabetic agents. With our ongoing interest towards aldose reductase (ALR2) inhibition, we have synthesized and screened a series of thiazoline derivatives (5a-k, 6a-f, 7a-1 & 8a-j) to find a lead as a potential new antidiabetic agent. The bioactivity results showed the thiazoline-based compound 7b having a benzyl substituent and nitrophenyl substituent-bearing compound 8e were identified as the most potent molecules with IC50 values of 1.39 ± 2.21 µM and 1.52 ± 0.78 µM respectively compared with the reference sorbinil with an IC50 value of 3.14 ± 0.02 µM. Compound 7b with only 23.4% inhibition for ALR1 showed excellent selectivity for the targeted ALR2 to act as a potential lead for the development of new therapeutic agents for diabetic complications.

Current Trends and Future Approaches in Small-Molecule Therapeutics for COVID-19.

The novel coronavirus (SARS-CoV-2) pandemic has created a global public health emergency. The pandemic is causing substantial morbidity, mortality and significant economic loss. Currently, no approved treatments for COVID-19 are available, and it is likely to takes at least 12-18 months to develop a new vaccine. Therefore, there is an urgent need to find new therapeutics that can be progressed to clinical development as soon as possible. Repurposing regulatory agency-approved drugs and experimental drugs with known safety profiles can provide important repositories of compounds that can be fast-tracked to clinical development. Globally, over 500 clinical trials involving repurposed drugs have been registered, and over 150 have been initiated, including some backed by the World Health Organisation (WHO). This review is intended as a guide to research into small-molecule therapies to treat COVID-19; it discusses the SARS-CoV-2 infection cycle and identifies promising viral therapeutic targets, reports on a number of promising pre-approved small-molecule drugs with reference to over 150 clinical trials worldwide, and offers a perspective on the future of the field.

Probing sulphamethazine and sulphamethoxazole based Schiff bases as urease inhibitors; synthesis, characterization, molecular docking and ADME evaluation.

In the current study, a novel series of Schiff base derivatives of (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (3a-3f) and (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (3g-3q) were synthesize. The structures of synthetic compounds were elucidated by various spectroscopic techniques such as FTIR, NMR and spectrometric HRMS analysis. Synthetic derivatives were evaluated for their Jack Bean urease inhibitory activity using established in-vitro assay. It is worth mentioning here that most of our derivatives of both series displayed moderate to strong inhibitory activity, ranging between IC50 = 2.48 ± 0.78 µM and 35.63 ± 1.26 µM, as compared to standard thiourea (IC50 = 20.03 ± 2.03 µM). Further, structure activity relationship studies suggest that the presence of halogen at ortho and para positions on the aryl ring in (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide derivatives and hydroxy and halogen in (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide derivatives increased the urease inhibitory activity. Furthermore, molecular docking studies were carried out in order to investigate the binding mode of this class of compounds to urease. In order to evaluate drug likeness of compounds ADME evaluation was done, and the synthesized compounds were found to be non-toxic and present passive gastrointestinal absorption. The data suggests the synthesized sulphamethazine and sulphamethoxazole derivatives can serve as a novel scaffold to inhibit urease.

Exploiting oxadiazole-sulfonamide hybrids as new structural leads to combat diabetic complications via aldose reductase inhibition.

A series of oxadiazole-sulfonamide hybrids was synthesized through multistep reaction and for the formation of targeted thioethers 6(a-l), a much facile route was adopted through which S-alkylation was successfully carried out at room temperature. These novel thioethers 6(a-l) were later screened against aldehyde reductase (ALR1) and aldose reductase (ALR2). Beside the enzyme inhibition studies, the compounds were also tested against cervical cancer cell lines (HeLa). The results suggested the significant inhibition pattern towards ALR2, while few compounds were active against ALR1. The synthesized derivatives have shown weak to moderate cytotoxicity. The most potent inhibitors (6b, 6e, 6f and 6l) were selected for molecular docking studies and the binding interactions were reported.

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 ±â€¯0.38, 3.55 ±â€¯0.26 and 1.37 ±â€¯0.92 µM, respectively, compared with sorbinil (IC50 = 3.14 ±â€¯0.02 µM). The compounds 3a, 3g, and 3m also inhibit ALR1 with IC50 value of 7.75 ±â€¯0.28, 7.26 ±â€¯0.39 and 7.04 ±â€¯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 ±â€¯0.92 µM for ALR2) and other two compound 3a and 3g could potentially lead for the development of new therapeutic agents.

Benzoxazinone-thiosemicarbazones as antidiabetic leads via aldose reductase inhibition: Synthesis, biological screening and molecular docking study.

Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ±â€¯0.04 and 0.19 ±â€¯0.03 µM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ±â€¯0.02 µM).

2-(Hetero(aryl)methylene)hydrazine-1-carbothioamides as potent urease inhibitors.

A small series of 2-(hetero(aryl)methylene) hydrazine-1-carbothioamides including two aryl derivatives was synthesized and tested for their inhibitory activity against urease. Compound (E)-2-(Furan-2-ylmethylene) hydrazine-1-carbothioamide (3f), having a furan ring, was the most potent inhibitor of urease with an IC50 value of 0.58 µM. Molecular modeling was carried out through docking the designed compounds into the urease binding site to predict whether these derivatives have analogous binding mode to the urease inhibitors. The study revealed that all of the tested compounds bind with both metal atoms at the active site of the enzyme. The aromatic ring of the compounds forms ionic interactions with the residues, Ala(440), Asp(494), Ala(636), and Met(637).