Compounds 4n Research Articles

6-Aminocoumarin oxime-ether/sulfonamides as selective hCA IX and XII inhibitors: Synthesis, evaluation, and molecular dynamics studies.

Carbonic anhydrase isoforms IX and XII are overexpressed in hypoxic tumor cells regulating various physiological processes such as cell proliferation, invasion, and metastasis, resulting in the onset and spread of cancer. Selective inhibition of these enzymes is a promising strategy for anticancer therapy. Coumarin derivatives were identified as selective and potent inhibitors of these isoforms. This study reports 6-aminocoumarin sulfonamide and oxime ether derivatives linked through a chloroacetyl moiety tethered to piperazine and piperidone, respectively, showing selective inhibition against human carbonic anhydrase (hCA) IX and XII with Ki ranging from 0.51 to 1.18 µM and 0.89-4.43 µM. While the sulfonamide derivative 8a exhibited submicromolar inhibition against hCA IX and XII with Ki 0.89 and 0.51 µM, the oxime ether derivatives showed lower activity than the sulfonamides, with the compound 5n inhibiting hCA IX and hCA XII with a Ki of 1.055 and 0.70 µM, respectively. The above results demonstrate the potential of these derivatives as selective, potent inhibitors of carbonic anhydrase IX and XII and provide a foundation for further optimization and development as effective anticancer agents. Further, the binding mode of the synthesized derivatives in the active site were examined using molecular docking and dynamic simulation studies.

Design, synthesis, in silico studies, and antidiabetic activity of several sulfanilamide incorporated 2,3-disubstituted thiazolidin-4-ones

A panel of 2,3-disubstituted thiazolidin-4-ones 4a-n was synthesised from Schiff bases 3a-n derived from sulfanilamide, by reaction with thioglycolic acid. The compounds were characterised by means of IR, NMR, and Mass spectral data. Compounds 4a-n were screened for DPPH scavenging assay and compounds 4e, 4h, 4i, and 4n exhibited moderate activity. Compounds 4e, 4h, and 4i were tested at 200 mg/kg and 4e at 50 mg/kg b.w. orally for antidiabetic activity in fructose induced diabetic rats. They exhibited significant antidiabetic activity compared to the control group. Pioglitazone was used as a standard drug. The tested compounds exhibited better and ignificant serum cholesterol lowering activity when compared with the control and standard groups. They also reduced the triglyceride level after the 21st day; however, it was insignificant when compared to the control group. Compound 4n displayed the highest binding energy when docked with PPAR-γ followed by compounds 4e, 4h, and 4i when compared to pioglitazone. The physicochemical, drug likeness and ADME properties of the title compounds were found to be satisfactory.

Synthesis, biological screening and in silico studies of new N-phenyl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine derivatives as potential antifungal and antitubercular agents

A new series of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) have been synthesized by a cyclo-condensation reaction of 2-bromo-1-(1,3-diphenyl-1H-pyrazol-4-yl)ethanone (6a-f) with N-aryl thiourea, (7a-d). The structure of newly synthesized N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives was analyzed by 1H NMR, 13C NMR and Mass spectral analysis. The compounds 8a-x were screened for in vitro antimicrobial activity against Escherichia coli, Proteus mirabilis, Bacillus subtilis, Staphylococcus aureus, Candida albicans and Aspergillus niger. and antitubercular activity against M. tuberculosis H37Rv strain. Among the twenty-four pyrazolyl-thiazole derivatives, six compounds 8a, 8b, 8j, 8n, 8o and 8s showed good activity against S. aureus. Against A. niger, all synthesized derivatives showed good antifungal activity. Fifteen pyrazolyl-thiazole derivatives 8a, 8f, 8g, 8h, 8j, 8k, 8n, 8o, 8p, 8q, 8r, 8s, 8t, 8w and 8x showed good antitubercular activity with MIC 1.80–7.34 μM (0.8–3.12 μg/mL), these derivatives have showed more activity than the drugs isoniazid and ethambutol. The active compounds were further screened for cytotoxicity activity against the mouse embryonic fibroblast cells (3t3l1) cell lines at 12.5 and 25 μg/mL concentrations and found less or non-cytotoxicity. To know the plausible mode of action, the synthesized pyrazolyl-thiazole derivatives were studied for pharmacokinetics, toxicity profiles and binding interactions along with an in-depth analysis of structural dynamics and integrity using prolonged molecular dynamics (MD) simulation. The compounds have shown significant docking scores in the range of −7.98 to −5.52 and −9.44 to −7.2 kcal/mol with the M. tuberculosis enoyl reductase (M. tb. InhA) and C. albicans sterol 14-α demethylase (C. ab. CYP51), respectively. Thus, the significant antifungal and antitubercular activity of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives incited that, these scaffolds could assist in the development of lead compounds to treat fungal and antitubercular infections.

Synthesis and biological evaluation of coumarine-imidazo[1,2-c][1,2,3]triazoles: PEG-400 mediated one-pot reaction under ultrasonic irradiation

Synthetic chemists have organized easy and effective ways for perfect synthesis in response to the requirement for scaffolds that are crucial for medical applications. To investigate the synthesis of fused 1,2,3-triazoles in the presence and absence of ultrasound, the [3 + 2] cycloaddition followed by CN bond formation reaction between 3-(iodoethynyl)-2H-chromen-2-one and substituted 2-chloro-N-phenylacetamides was carried out under relatively optimized conditions. The cancer activity of the synthesized compounds were then tested in vitro against two MCF-7 and A-549 and the majority of the examined compounds 4e-4o showed significant activity, with compounds 4f, 4 g, and 4 h surpassing the standard drug against the A-549 line, and 4 m and 4n excelling it against MCF-7. Later, in vitro EGFR results revealed that compounds 4f (IC50 = 0.420 ± 0.08 μM), 4 g (IC50 = 0.367 ± 0.02 μM), and 4 h (IC50 = 0.453 ± 0.02 μM) were more effective than the conventional medicine Erlotinib (IC50 = 0.460±0.06 μM). In silico investigations of more potent compounds (4f, 4 g, 4 h, 4i, 4k, 4 m, and 4n) and erlotinib on the EGFR protein indicated that all seven compounds had much higher binding energies and inhibition constants than the erlotinib. Finally, the in silico pharmacokinetic profile of compounds 4f, 4 g, 4 h, 4i, 4k, 4 m, and 4n was estimated using SWISS/ADME and pkCSM, where all compounds followed Lipinski, Veber, Egan, and Muegge rules without deviation.

Design, synthesis and antimicrobial evaluation of benzimidazole containing 4-thiazolidinone based 5-arylidene derivatives

In an attempt to design a potent class of antimicrobials, we have synthesized benzimidazole derivatives based on 4-thiazolidinone which possessed 5-arylidenes 5a-o by using different catalysts under multistep conventional synthesis. Structures of the synthesized compounds have been established based on spectral data and compounds have been screened for their antimicrobial activity. Compound 5j shows maximum potency against all Gram-positive bacteria with a minimum inhibitory concentration (MIC) in the range of 25-50 μg/mL while moderate activity against Gram-negative bacterial strains is observed with a MIC value of 62.50 μg/mL. Compound 5n is found to be the most active against fungal strains with a MIC value of 250 μg/mL.

Triple targeting of mutant EGFRL858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFRL858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFRL858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.

Synthesis and Evaluation of Piperazine-Tethered Derivatives of Alepterolic Acid as Anticancer Agents.

Alepterolic acid is a natural diterpenoid isolated from Aleuritopteris argentea with potential anti-cancer activity. In this study, alepterolic acid was modified to construct a series of arylformyl piperazinyl derivatives (3a-3p). The synthesized derivatives were fully characterized with HRMS, NMR, and IR. Four compounds with inhibition rate higher than 30 % at 10 μM (3f, 3n, 3g and 3k) were further measured to obtain the IC50 values against four cancer cell lines, including hepatoma cell lines HepG2, lung cancer cell lines A549, estrogen receptor-positive cell lines MCF7, and triple-negative breast cancer (TNBC) cell lines MDA-MB-231 by MTT assay. It was found that these compounds were more effective to HepG2 and MDA-MB-231 cells, while less toxic to A549 and MCF7 cells, and compound 3n as the most toxic derivatve against MDA-MB-231 cell lines, with IC50 value of 5.55±0.56 μM. Trypan blue staining and colony formation assay showed that compound 3n inhibited the growth of MDA-MB-231 cells and prevented colony formation. Hoechst staining, flow cytometry and western blot analysis revealed that compound 3n induced caspase-dependent apoptosis in MDA-MB-231 cells. Conclusively, compound 3n was demonstrated to be a potential anti-cancer lead compound for further investigation.

Novel Matrine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, and Mechanistic Analysis.

A large number of studies have shown that matrine (MA) possesses various pharmacological activities and is one of the few natural, plant-derived pesticides with the highest prospects for promotion and application. Fifty-eight MA derivatives were prepared, including 10 intermediates and 48 target compounds in 3 series, to develop novel mosquitocidal agents. Compounds 4b, 4e, 4f, 4m, 4n, 6e, 6k, 6m, and 6o showed good larvicidal activity against Aedes albopictus, which is both a highly aggressive mosquito and an important viral vector that can transmit a wide range of pathogens. Dipping methods and a bottle bioassay were used for insecticidal activity evaluation. The LC50 values of 4e, 4m, and 6m reached 147.65, 140.08, and 205.79 μg/mL, respectively, whereas the LC50 value of MA was 659.34 μg/mL. Structure-activity relationship analysis demonstrated that larvicidal activity could be improved by the unsaturated heterocyclic groups introduced into the carboxyl group after opening the D ring. The MA derivatives with oxidized N-1 lost their mosquitocidal activities, indicating that the bareness of N-1 is crucial to maintain their anti-mosquito activity. However, the activity was not greatly influenced by introducing a cyan group at C-6 or a benzene sulfonyl group at N-16. Additionally, compounds 4e and 4m exhibited good inhibitory activities against acetylcholinesterase with inhibitory rates of 59.12% and 54.30%, respectively, at a concentration of 250 μg/mL, whereas the inhibitory rate of MA was 9.88%. Therefore, the structural modification and mosquitocidal activity of MA and its derivatives obtained here pave the way for those seeking strong mosquitocidal agents of plant origin.

Investigations of p-tolyloxy-1,3,4-oxadiazole propionamides as soybean 15-lipoxygenase inhibitors in comforting with in vitro and in silico studies

Inflammatory disorders are the prime contributor to public health issue and the development of more effective and safer anti-inflammatory drugs in addition to other therapeutic alternatives to treat inflammatory illnesses, particularly chronic inflammatory diseases, is one of the foremost current issues. In this regard, our present work is concerned with the synthesis of a new series of N-alkyl/aralkyl/aryl derivatives (7a–o) of 5-((p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-ylthio)propionamide which was instigated by the successive conversions of p-tolyloxyacetic acid into ester, hydrazide and 5-(p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-thiol. The planned compounds (7a–o) were attained by the reaction of 5-(p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-thiol with variety of N-alkyl/aralkyl/aryl electrophiles in potassium hydroxide and were characterized by FTIR, 1H-, 13C-NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and probed for their inhibiting potential against soybean 15-lipoxygenase (15-LOX) enzyme. The compounds 7a, 7n, 7 g, 7e, 7h, 7i, 7j and 7b promulgated the potent inhibiting potential with IC50 values 9.43 ± 0.45, 16.75 ± 0.49, 19.45 ± 0.37, 21.32 ± 0.46, 22.64 ± 0.56, 23.53 ± 0.62, 24.32 ± 0.45 and 29.15 ± 0.57 µM, respectively, while excellent to good inhibitory activities were shown by 7o, 7 m, 7k, 7f, 7c, 7 l and 7d with IC50 values in the range 30.29 ± 0.56 to 52.54 ± 0.64 µM. Compounds 7i–o maintained 91.12 ± 1.5 to 98.23 ± 1.2% blood mononuclear cells (MNCs) viability at 0.25 mM by MTT assay whilst compounds 7d–h observed 46.51 ± 1.3 to 57.12 ± 1.4% viability where as the most toxic compounds were 7b (12.51 ± 1.4%), 7a (28.12 ± 1.5%) and 7c (38.23 ± 1.5%) as compared with controls. Pharmacokinetic profiles predicted good oral bioavailability and drug-likeness properties of molecules as per rule of five. Molecular docking studies displayed hydrogen bonding between the compounds and the enzyme with Arg378 which was common in 7n, 7 g, 7h and baicalein. In 7a and quercetin, hydrogen bonding was established through Asn375; Tyr512 and Val589 were also involved in bonding with other analogues. RMSD (root mean square deviation) values exhibited good inhibitory profiles in the order quercetin (0.73 Å)<7 g (0.98 Å)<baicalein (1.23 Å)<7a (1.27 Å)<7n (1.75 Å)<7h (1.81 Å) whereas the binding free energies (kJ/mol) increasing order: (−37.56 kJ/mol)< quercetin (−35.43 kJ/mol)<7n (−34.55 kJ/mol)<7 g (−33.38 kJ/mol)<7h (31.75 kJ/mol)<7a (−31.63 kJ/mol). Density functional theory (DFT) data established good correlation between the IC50 values of compounds and HOMO–LUMO (highest occupied and lowest unoccupied molecular orbitals) energy calculations. It was found that compounds with more stabilized LUMO orbitals had significant biological activity. The work collectively supports steps taken forward in search for potential ‘leads’ as anti-inflammatory agents wherein compounds 7a, 7n, 7i, 7j possessed ‘lead’ like properties for further investigations. Communicated by Ramaswamy H. Sarma

Synthesis Anticonvulsant and Cytotoxic Evaluation of Benzimidazole-Quinoline Hybrids Schiff Base Analogs

Both, benzimidazole and quinoline pharmacophores have shown various activities against cancer, tuberculosis, malaria, fungal, viral, and bacterial infections. These moieties are considered highly potent nuclei in medicinal chemistry. Thus, this research work aims to produce a synergistic effect involving both nuclei in a single structure. A Series of literature work resulted in the synthesis of novel derivatives of 2‐(1H‐1,3‐benzothiazole‐2‐yl)‐N'‐substituted quinoline‐4‐carbohydrazide 5a–q using a multiple-step reaction. Characterization of all compounds was successfully done using IR and 1HNMR, 13CNMR as well as elemental analysis. Furthermore, screening of all synthesized compounds has been shown a positive response as an anticonvulsant and antidepressant activity in mice. Compounds 5b, 5h, 5l, and 5n have shown potentially active on pentylenetetrazole-induced seizures in mice. The synthesized compounds were also screened on a panel of 60 cell lines by the National Cancer Institute according to standard screening protocol. Ten compounds were selected and evaluated via a single high dose (10−5 M). In a one-dose assay, compounds 5j and 5o showed the highest activity on leukemia (CCRF-CEM) and renal cancer (A498) with growth inhibition (GI) of 70.91 and 61.15%.

Design, Synthesis, and Anti-Bacterial Evaluation of Tetrahydrobenzothiophene Derivatives as Lipopolysaccharide Biogenesis Inhibitors

Background: Bacterial infections caused by multidrug-resistant bacteria have emerged as major threats to human communities worldwide. There is a great need to develop new mechanisms by which anti-bacterial agents can combat bacterial antibiotic resistance. Objective: This study aims to synthesize and characterize a series of novel tetrahydrobenzothiophene derivatives and evaluate their anti-bacterial activities. Method: In this study, we have synthesized 2-benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid derivatives (3a-3r) and investigated their anti-bacterial activities against E. coli, P. aeruginosa, Salmonella, and S. aureus. Results: The MIC values demonstrated that all synthesized derivatives possessed potent anti-bacterial activity properties. Compounds 3b, 3e, 3f, 3g, 3h, 3n, and 3q exhibited in vitro excellent anti-bacterial efficiency. Compounds 3b, 3e, 3f, and 3p were evaluated by in vitro time-kill assay; they displayed concentration- dependent bacteriostatic effects. Compounds 3b, 3e, 3f, and 3p showed moderate water solubility, high stability in plasma, and moderate acute oral toxicity. Conclusion: Most of the 2-benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid derivatives exhibited potent anti-bacterial activities. The data reported in this paper may guide the design of tetrahydrobenzothiophene derivatives.

Design and Metal-Free Synthesis and Cytotoxicity Evaluation of 5Hchromeno[ 4,3-b]pyridine Derivatives as Anti-Proliferative Agents

Background:A novel metal-free approach is reported for the synthesis of 5H-chromeno[4,3-b]pyridine derivatives. Indeed, chromene derivatives are found to exhibit a broad spectrum of biological activities such as antibacterial, antirhinovirus, antioxidant, cytotoxic, anticancer, and antimicrobial properties.Methods:This method provides an easy access to a large number of 5H-chromeno[4,3-b]pyridine scaffolds by the condensation of 3-formylchromene with -enaminoesters under thermal conditions. All compounds are well characterized by NMR, IR and mass spectrometry. This is a safe and convenient protocol.Results:Thus newly synthesized compounds are evaluated for their cytotoxicity against four human cancer cell lines, such as B16 (Skin cancer), DU145 (Prostate cancer), Hela (Cervical cancer) and CHO (Chinese hamster ovary).Conclusion:Among them, compounds 3n and 3o shows an excellent anti-proliferation activity against CHO (IC50 12.33+1.13 μM), Hela (IC50 22.33+0.51 μM), and B16 (IC50 27.61+0.8 μM) cell lines, while compounds 3c, 3g and 3q exhibits promising anti-proliferation against above four human cancer cell lines with IC50 14.96+1.9, 15.59+0.9, 13.8+0.06 μM, respectively, compared with a standard drug Doxorubicin &amp; Mitomycin.

Ultrasound assisted Cu-catalyzed Ullmann-Goldberg type coupling-cyclization in a single pot: Synthesis and in silico evaluation of 11H-pyrido[2,1-b]quinazolin-11-ones against SARS-CoV-2 RdRp

The in silico evaluation of 11H-pyrido[2,1-b]quinazolin-11-one derivatives against SARS-CoV-2 RdRp was undertaken based on the reports on antiviral activities of this class of compounds in addition to the promising interactions of the antiviral drug penciclovir as well as quinazoline derivatives with SARS-CoV-2 RdRp in silico. The target compounds were prepared via an Ullmann–Goldberg type coupling followed by the subsequent cyclization (involving amidation) in a single pot. The methodology involved a CuI-catalyzed reaction of 2-iodobenzoate ester with 2-aminopyridine or quinolin-2-amine or thiazol-2-amine under ultrasound to give the expected products in acceptable (51–93%) yields. The molecular interactions of the synthesized 11H-pyrido[2,1-b]quinazolin-11-one derivatives with the SARS-CoV-2 RdRp (PDB: 7AAP) were evaluated in silico. The study suggested that though none of these compounds showed interactions better than penciclovir but the compound 3a and 3n appeared to be comparable along with 3b seemed to be nearly comparable to favipiravir and remdesivir. The compound 3n with the best binding energy (-79.85 Kcal/mol) participated in the H-bond interactions through its OMe group with THR556 as well as ARG624 and via the N-5 atom with the residue SER682. The in silico studies further suggested that majority of the compounds interacted with the main cavity of active site pocket whereas 3h and 3o that showed relatively lower binding energies (-66.06 and -66.28 Kcal/mol) interacted with the shallow cavity underneath the active site of SARS CoV-2 RdRp. The study also revealed that a OMe group was favourable for interaction with respect to its position in the order C-8 > C-1 > C-2. Further, the presence of a fused quinoline ring was tolerated whereas a fused thiazole ring decreased the interaction significantly. The in silico predictions of pharmacokinetic properties of 3a, 3b and 3n indicated that besides the BBB (Blood Brain Barrier) penetration potential these molecules may show a good overall ADME. Overall, the regioisomers 3a, 3b and 3n have emerged as molecules of possible interest in the context of targeting COVID-19.

Synthesis and biological evaluation of pyrazole-fused oleanolic acid derivatives as novel inhibitors of inflammatory and osteoclast differentiation

A series of pyrazole-fused oleanolic acid derivatives were designed and synthesized. The modification of these analogues focused on the substituents screening on the pyrazole ring. The cytotoxicity of these compounds and their anti-inflammatory activities via inhibiting interleukin-1β (IL-1β) production were evaluated in RAW264.7 cells. Most of the derivatives showed significantly improved potency compared with oleanolic acid. Among them, compound 7n exhibited the most potent anti-inflammatory activity on decreasing IL-1β production with low cytotoxicity. Moreover, the further study found 7n could inhibit RANKL-induced osteoclast differentiation on bone marrow-derived macrophages (BMMs). These findings may provide a potential direction for the drug development of osteoarthritis.

Design, Synthesis and Molecular Docking of 1,3,4-Oxadiazole-2(3H)-thione Derivatives Containing 1,4-Benzodioxane Skeleton as Potential FabH Inhibitors.

Fatty acid biosynthesis is essential for bacterial survival. Of these promising targets, β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target. A series of novel 1,3,4-oxadiazole-2(3H)-thione derivatives containing 1,4-benzodioxane skeleton targeting FabH were designed and synthesized. These compounds were determined by 1 H-NMR, 13 C-NMR, MS and further confirmed by crystallographic diffraction study for compound 7m and 7n. Most of the compounds exhibited good inhibitory activity against bacteria by computer-assisted screening, antibacterial activity test and E. coli FabH inhibitory activity test, wherein compounds 7e and 7q exhibited the most significant inhibitory activities. Besides, compound 7q showed the best E. coli FabH inhibitory activity (IC50 =2.45 μΜ). Computational docking studies also showed that compound 7q interacts with FabH critical residues in the active site.

Identification of New N-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors

Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer's disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC50 of 0.71 μM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC50 = 1.11 μM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with Ki values of 0.21 and 0.28 μM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC50 of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC50 of 1.19-3.87 μM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (-11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood-brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases.

New thioxothiazolidinyl-acetamides derivatives as potent urease inhibitors: design, synthesis, in vitro inhibition, and molecular dynamic simulation

To identify potent urease inhibitors, in the current study, a series of thioxothiazolidinyl-acetamides were designed and synthesized. The prepared compounds were characterized by spectroscopic techniques, including FTIR, 1HNMR, 13CNMR, and elemental analysis. In the enzymatic assessments, it was demonstrated that all derivatives had significant urease inhibition with IC50 values in the range of 1.473–9.274 µM in comparison with the positive control hydroxyurea (IC50 = 100.21 ± 2.5 µM) and thiourea (IC50 = 23.62 ± 0.84 µM). Compound 6i (N-benzyl-3-butyl-4-oxo-2-thioxothiazolidine-5-carboxamide) was the most active agent with an IC50 value of 1.473 µM. Additionally, kinetic investigation and in silico assessments of 6i was carried out to understand the type of inhibition and behavior of the most potent derivative within the binding site of the enzyme. Noteworthy, the anti-urease assay against P. vulgaris revealed 6e and 6i as the most active agents with IC50 values of 15.27 ± 2.40 and 17.78 ± 3.75 µg/mL, respectively. Antimicrobial evaluations of all compounds reveal that compounds 6n and 6o were the most potent antimicrobial agents against the standard and resistant S. aureus. 6n and 6o also showed 37 and 27% inhibition in the development of biofilm by S. aureus at 512 µg/ml. Furthermore, the MTT test showed no toxicity up to 100 µM. Taken together, the study suggests that the synthesized thioxothiazolidinyl-acetamides bases derivatives may serve as potential hits as urease inhibitors.

New supramolecules of bis(acylhydrazones)-linked bisphenol sulfide for Alzheimer's: targeting cholinesterases by in vitro and in silico approaches.

In current research, two functional components, i.e., hydrazone and bisphenol sulfide were combined to get useful supramolecules in medicinal chemistry. Herein 25 new 4,4'-thiodiphenol bis-acylhydrazones were synthesized in good to excellent yields. Initially ethyl-2-chloroacetate was reacted with 4,4'-thiodiphenol, which was further reacted with excess hydrazine hydrate to produce 2,2'-((thiobis(4,1-phenylene))bis(oxy))di(acetohydrazide), which was then combined with various aromatic and aliphatic aldehydes to get the desired products (hydrazones, 4a-4y). The synthesized supramolecules were characterized by contemporary spectroscopic techniques such as 1H NMR, 13C NMR, and mass spectroscopy. The synthetic compound's cholinesterase blocking activity was tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes where compounds 4n, and 4h showed excellent inhibitory potential for AChE, while 4b, and 4h, demonstrated most potent inhibition of BChE. The starting compound (SM3) and compounds 4h and SM3 depicted excellent dual inhibitory capabilities for both enzymes. The chemical basis of anticholinesterase activity was investigated using a structure-based molecular docking approach. The biological significance and the ease of synthesis of this class of compounds should be considered in therapeutic development for Alzheimer's disease treatments.

New nitazoxanide derivatives: design, synthesis, biological evaluation, and molecular docking studies as antibacterial and antimycobacterial agents.

A new series inspired by combining fragments from nitazoxanide (NTZ) and 4-aminosalicylic acid (4-ASA) was synthesized and screened for in vitro antibacterial and antimycobacterial activities. The majority showed higher antibacterial potency than NTZ against all the screened strains, notably, 5f, 5j, 5n and 5o with MICs of 0.87-9.00 μM. Compounds 5c, 5n and 5o revealed higher potency than ciprofloxacin against K. pneumoniae, while 5i was equipotent. For E. faecalis, 3b, 5j, and 5k showed higher potency than ciprofloxacin. 5j was more potent against P. aeruginosa than ciprofloxacin, while 5n was more potent against S. aureus with an MIC of 0.87 μM. 5f showed equipotency to ciprofloxacin against H. pylori with an MIC of 1.74 μM. Compounds 3a and 3b (4-azidoNTZ, MIC 4.47 μM) are 2 and 5-fold more potent against Mycobacterium tuberculosis (Mtb H37Rv) than NTZ (MIC 20.23 μM) and safer. 4-Azidation and/or acetylation of NTZ improve both activities, while introducing 1,2,3-triazoles improves the antibacterial activity. Molecular docking studies within pyruvate ferredoxin oxidoreductase (PFOR), glucosamine-6-phosphate synthase (G6PS) and dihydrofolate reductase (DHFR) active sites were performed to explore the possible molecular mechanisms of actions. Acceptable drug-likeness properties were found. This study may shed light on further rational design of substituted NTZ as broad-spectrum more potent antimicrobial candidates.

Discovery of reversible selective monoamine oxidase B inhibitors with anti-acetylcholinesterase activity derived from 4-oxo-N-4-diphenyl butanamides.

Aim: Multitargeted drugs are essential for the treatment of various neurodegenerative disorders, because of their complex nature. This study aimed to develop novel small molecules as selective monoamine oxidase B (MAO-B) inhibitors with cholinesterase inhibition. Materials & methods: With the help of fragment-based drug design, some 4-oxo-N-4-diphenyl butanamides were designed and synthesized as MAO-B inhibitors with anti-acetylcholinesterase (AChE) activity. Results: Compound 6m showed the best neuroprotection, with reversible selective MAO-B inhibition activity (IC50 = 11.54±0.64nM). Compounds 6b, 6h, 6j, 6n and 6p (IC50 = 20.90±0.50, 17.25±0.90, 15.85±0.16, 16.81±0.85 and 25.19±0.17nM, respectively) also appeared as potent and selective MAO-B inhibitors with anti-AChE activity. Conclusion: The present study suggests potent, neuroprotective and nontoxic lead compounds as selective MAO-B inhibitors with anti-AChE activity.