Compounds 4d Research Articles

Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease.

The main protease Mpro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported Mpro inhibitors was the peptidomimetic α-ketoamide 13b, whose cocrystal structure with Mpro paved the way for multiple lead-finding studies. We established structure-activity relationships for the 13b series by modifying residues at the P1', P3, and P4 sites. Guided by cocrystal structures, we reduced the P1' substituent size to better fill the pocket and added a fluorine substituent to the pyridone ring, enabling a new hydrogen bond with Gln189 in P3. Among 22 novel analogues, 6d and 12d inhibited Mpro with IC50s of 110 nM and 40 nM, improving the potency of 13b by up to 9.5-fold. Compound 6d had pronounced antiviral activity with an EC50 of 1.6 μM and was stable in plasma and microsomes. The study illustrates the potential of structure-based design to systematically improve peptidomimetic α-ketoamides.

Comparative Analyses of Antiviral Potencies of Second-Generation Integrase Strand Transfer Inhibitors (INSTIs) and the Developmental Compound 4d Against a Panel of Integrase Quadruple Mutants

Second-generation integrase strand transfer inhibitors (INSTIs) are strongly recommended for people living with HIV-1 (PLWH). The emergence of resistance to second-generation INSTIs has been infrequent and has not yet been a major issue in high-income countries. However, the delayed rollouts of these INSTIs in low- to middle-income countries during the COVID-19 pandemic combined with increased transmission of drug-resistant mutants worldwide are leading to an increase in INSTI resistance. Herein, we evaluated the antiviral potencies of our lead developmental INSTI 4d and the second-generation INSTIs dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) against a panel of IN quadruple mutants. The mutations are centered around G140S/Q148H, including positions L74, E92, and T97 combined with E138A/K/G140S/Q148H. All of the tested INSTIs lose potency against these IN quadruple mutants compared with the wild-type IN. In single-round infection assays, compound 4d retained higher antiviral potencies (EC50 values) than second-generation INSTIs against a subset of quadruple mutants. These findings may advance understanding of mechanisms that contribute to resistance and, in so doing, facilitate development of new INSTIs with improved antiviral profiles.

Design and synthesis of new 1,2,3-triazole derivatives as VEGFR-2/telomerase downregulatory candidates endowed with apoptotic potential for cancer treatment.

In this current work, we dedicated efforts to designing and synthesizing new 1,2,3-triazole-analogues (5a-d), (6a-d), and (7a-c) to act as dual VEGFR-2 and telomerase inhibitors with promising apoptotic potential. The synthesized analogues were examined against eleven diverse types of cancer cells and two normal cells to assess their ability to inhibit cell growth (GI%). Obviously, compound 7b showed the best average GI% (75.69%) surpassing the average GI% of Dox (65.79%). Compound 5d showed the lowest IC50 values (25.86 and 51.91µM) against HNO-97 and FaDu cancer cells, respectively. Besides, compound 5a exhibited the lowest IC50 value (15.46µM) against HCT116, whereas compound 6b revealed the lowest IC50 value (31.14µM) against HuH7. Besides, candidates 5a, 5b, 5d, and 7a showed prominent inhibitory results towards VEGFR-2 protein with decreasing its expression by 0.33, 0.42, 0.38 and 0.26-fold change, respectively. However, compounds 5a, 5b, 5d, and 7a showed promising inhibitory results towards telomerase protein and decreased its expression by 0.60, 0.50, 0.52, and 0.44-fold change, respectively. Additionally, it was clear that compound 5a was able to upregulate the expression of Caspases 3, 8, and 9 proteins by 2.19, 1.83, and 1.62-fold change, respectively. Besides, 5a was able to downregulate the expression of CDK-2, CDK-4, and CDK-6 proteins by 0.50, 0.43, and 0.13-fold change, respectively. Obviously, compound 5a halted the cell cycle at the G1, S, and G2-M phases in HCT116 cells. Subsequently, the synthesized 1,2,3-triazole analogues can be treated as lead VEGFR-2 and telomerase inhibitors with potential apoptotic activity for future optimization and cancer treatment.

Design, Synthesis, Biological Evaluation and Docking Studies of 2-hydroxy-4-benzyloxy Chalcone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, but no drugs can cure this disease. Chalcones possess good antioxidant activity, anti-neuroinflammatory activity, neuroprotective effects, inhibitory effects on Aβ aggregation, and Aβ disaggregation ability. Therefore, chalcones are ideal lead compounds, and the discovery of novel anti-AD agent-based chalcones is necessary. Hydroxy groups and aryl benzyl ether groups were introduced into chalcone scaffolds to obtain a series of 2-hydroxyl-4-benzyloxy chalcone derivatives. These derivatives were further synthesized, biologically evaluated, and docked. Most target derivatives exhibited good anti-AD activities. In particular, compound 11d had excellent inhibitory effects on self-induced Aβ1-42 aggregation (90.8% inhibition rate at 25 μM) and Cu2+ induced Aβ1-42 aggregation (93.4% inhibition rate at 25 μM). In addition, it also exhibited good Aβ1-42 fibril disaggregation ability (64.7% at 25 μM), significant antioxidative activity (ORAC = 2.03 Trolox equivalent), moderate MAO-B inhibition (IC50 = 4.81 μM), selective metal chelation, appropriate BBB permeation, and dramatic anti-neuroinflammatory ability. In addition, compound 11d relieved AD symptoms and protected hippocampal neurons in vivo. Compound 11d is a promising multifunctional anti-Aβ agent.

Synthesis and Apoptotic Effects of DNMT Inhibition Targeted Novel Hybrid Molecules Bearing Thiadiazole and Clopidogrel for Cancer Treatment

Despite the efforts to treat cancer with chemotherapeutic agents targeting different mechanisms, cancer is still one of the most important health problems today. The increase in cancer incidence has led researchers to discover new, effective, and selective molecules. For this purpose, novel thiosemicarbazide (3a–3i) and 1,3,4-thiadiazole derivatives (4a–4i) were synthesized from clopidogrel bisulfate and their cytotoxic activities were investigated against glioblastoma (U87) cell line and healthy fibroblast (L929) cell line by MTT assay. Among the synthesized compounds; 3b, 3g, 4b, 4d, and 4i exhibited higher cytotoxic activities than the standard drug paclitaxel against U87 cancer cells. Cell apoptosis was detected by Bax, Bcl-2, caspase-3 activity, and Annexin V assay. The results displayed that compounds 3b, 3g, 4b, 4d, and 4i induced apoptosis in U87 cells. Moreover, all compounds were investigated for DNA methyltransferase (DNMT) activity in U87 cells. DNMT enzyme activity was decreased in these compounds’ treated cells. Cyclohexyl ring-bearing compound 4d, which showed the highest activity against U87 cells, was the most potent inhibitor of DNMT with an IC50 value of 5.78 ± 1.07 µM compared to paclitaxel (82.05 ± 4.67 µM). Molecular docking studies were also performed to identify the interactions between the compounds and the active sites of DNMT.

New Pyranopyrazole-Based Indolin-2,3-dione Hybrid as Effective Inhibitors of Xanthine Oxidase: Synthesis, In Vitro, and Molecular Modelling Approaches.

In the current study, new pyranopyrazole analogues (9a-d and 10a-d) were synthesized through a one-pot condensation reaction of 2-arylacetohydrazide. The inhibitory abilities were investigated against the XO enzyme through experimental and molecular docking analyses. The synthesis studies were based on ultrasound-mediated condensation reactions of four-component systems containing 2-arylacetohydrazide, ethyl acetoacetate, indoline-2,3-dione, and ethyl 2-cyanoacetate/malononitrile in various solvents and catalysts to yield pyranopyrazole analogues (9a-d and 10a-d) in a short reaction time and remarkably favorable yields ranging from 79-92%. Based on the XO inhibition study of compounds 9a-d and 10a-d, compound 10d was the most potent (IC50 = 0.09 ± 0.22 µM), followed by 9c (0.12 ± 0.11 µM). With IC50 values of 0.20 ± 0.27 µM and 0.17 ± 0.11 µM respectively, compounds 10a and 10c exhibited moderate activity. The other compounds have shown less activity compared to the allopurinol control (IC50 = 0.14 ± 0.10 µM). Furthermore, in the molecular docking analysis, compound 10d was predicted to have the highest binding affinity against the target XO enzyme.

Sulphonyl thiourea compounds containing pyrimidine as dual inhibitors of I, II, IX, and XII carbonic anhydrases and cancer cell lines: synthesis, characterization and in silico studies.

Some novel sulphonyl thiourea derivatives (7a-m) containing 4,6-diarylpyrimidine rings were designed and synthesized using a one-pot procedure. These compounds exhibited remarkable dual inhibitory activity against human carbonic anhydrase hCA I, hCA II, hCA IX, and XII isoenzymes and some cancer cell lines. Among them, some thioureas had significantly more potent inhibitory activities in the order of 7l > 7c > 7f (against the hCA I isoform), 7f > 7b > 7c (against the hCA II isoform), 7c > 7g > 7a > 7b (against the hCA IX isoform), and 7d > 7c > 7g > 7f (against the hCA XII isoform). The obtained inhibitory activity data against the hCA IX and XII isoforms showed that compound 7c was the most potent inhibitor in this sulphonyl thiourea series against enzyme hCA IX, with K I = 125.1 ± 12.4 nM, while compound 7d was the most potent inhibitor against enzyme hCA XII, with K I = 111.0 ± 12.3 nM. Compound 7c exhibited strong inhibitory activity among all four tested hCA enzymes, while thiourea 7f was a potent inhibitor for enzymes hCA I, II and XII. All these compounds demonstrated non-competitive inhibition of both enzymes. Some selected potential inhibitory compounds, including 7c, 7d, and 7g, exhibited remarkable cytotoxic activity against human cancer cell lines, including human breast adenocarcinoma (MCF-7), human liver adenocarcinoma (HepG2), human cervical epithelial carcinoma (HeLa), and human lung adenocarcinoma cells (A549). These compounds exhibited low cytotoxicity in the WI-38 cell line. The compounds 7c and 7d were the most potent inhibitors against tumour-associated hCA IX and hCA XII isoenzymes. Furthermore, these compounds exhibited remarkable inhibition against some cancer cell lines, such as MCF-7, HepG2, HeLa, and A549. They were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of in vitro and in silico studies revealed that compounds 7c and 7d were the most promising derivatives in this series owing to their significant effects on the studied hCA IX and hCA XII isoenzymes, respectively. The results showed that the sulphonyl thiourea moiety was deeply accommodated in the active site and interacted with zinc ions in the receptors.

Synthesis, biological evaluation and molecular docking studies of flavonol-3-O-β-D-glycoside as a potential inhibitor of SARS-CoV-2 main protease (3CLpro) in drug development for COVID-19.

The COVID-19 pandemic began in March 2020 and has affected many countries and infected over a million people. It has had a serious impact on people's physical and mental health, daily life and the global economy. Today, many drugs show limited efficacy in the treatment of COVID-19 and studies to develop effective drugs continue. Here, we aim to the synthesise and characterise of the flavonol-3-O-glycoside derivatives, the following and evaluated molecular docking studies with antimicrobial activity, inhibition of SARS-CoV-2 main protease enzyme (3CLpro) and nuclease activity. Molecular docking simulations of the synthesized flavonol-3-O-glycoside derivatives, especially compounds 5a, 5d, 5h, 5i and 5m, showed a stronger interaction with SARS-CoV-2 3CLpro in the active site. Two compounds from the target compounds, 5h and 5m, were found to be specifically effective against M. smegmatis and yeasts. In particular, compounds 5a, 5d, 5h, 5i and 5m, which exhibited high activity against the SARS-CoV-2 main protease enzyme, were found to be effective at low concentrations. We determined the IC50 values for the compounds that showed an inhibitory effect as well as their nuclease activities, which further emphasising the potential of our results. Among these, compound 5d showed a significant competitive inhibitor of 3CLpro. Furthermore, nuclease activity studies identified compound 5d as the most potent. The above results suggest that the flavonol-3-O-glycoside derivatives could be promising new antiviral agents for the development of 3CLpro inhibitors to combat COVID-19.

New 1,3,4‒oxadiazole Quinazolines as Potential Anticancer Agents: Design, Synthesis, Biological Evaluation, and In silico Studies.

A novel series of 1,3,4‒oxadiazole connected to derivatives of quinazolinone (7a-e and 8a-f) was synthesized in the current investigation, and its anticancer and Topoisomerase‒ II inhibitory activity was evaluated. These findings inspired the design, synthesis, and biological analysis of these 1,3,4‒oxadiazole-quinazolinone analogues as antiproliferative Topo‒II inhibitors. The novel compound structures were determined using mass spectrometry and spectral methods (IR, NMR: 1H & 13C). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colourimetric assay has been used to evaluate the anticancer efficacy of these drugs, and Autodock 4.2 provides a description of the docking results. For the more active members, additional biological tests, such as the Topo‒II inhibition experiment, were performed. These compounds' physicochemical and ADMET characteristics were examined in more detail. In the experiment for antiproliferative activity, compounds 7d, 7e, 8c, 8e, and 8f demonstrated encouraging cytotoxicity findings against HCT‒116 and HepG2 cancer cell lines, with IC50 values ranging from 3.85 to 19.43 μM. Compounds 7d, 7e, and 8e were the most potent inhibitors of Topo II with IC50 values of 15.18, 17.55, and 12.59 μM, respectively. Additionally, the docked compound 8c showed the strongest conventional hydrogen bonds among the residues Leu507(B), Asn508(B), Asn520(B), and Glu522(B) in the Human topoisomerase‒IIβ active site in the DNA complex (4G0U) when compared to the findings of docking experiments. New findings have discovered the fact that fused 1,3,4‒oxadiazole bearing quinazolinone contributed great significance in the field of medicinal chemistry due to their diverse biological properties. Finally, the in silico pharmacokinetic profile of all the synthesized derivatives was estimated using SwissADME, where some of the compounds followed Lipinski, Veber, Egan, and Muegge rules without deviation. The result of this activity advises that with a simple modification in structure, a potent anticancer agent can be generated with good efficacy.

Design, synthesis, and biological evaluation of pyrazole-ciprofloxacin hybrids as antibacterial and antibiofilm agents against Staphylococcus aureus.

In our continued efforts to tackle antibiotic resistance, a new series of pyrazole-ciprofloxacin hybrids were designed, synthesized, and evaluated for their antibacterial activity against Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Mycobacterium tuberculosis (Mtb). Most of the compounds exhibited good to excellent activities against S. aureus, and six compounds (7a, 7b, 7d, 7g, 7k, and 7p) exhibited higher or comparable activity (MIC = 0.125-0.5 μg mL-1) to ciprofloxacin (0.125 μg mL-1). Further, these selected compounds were non-toxic (CC50 ≥ 1000 μg mL-1) when evaluated for cell viability test against the Hep-G2 cell line. Three compounds (7a, 7d, and 7g) demonstrated excellent activity against ciprofloxacin-resistant S. aureus with MIC values ranging from 0.125-0.5 μg mL-1 and good antibiofilm activity. Among them, 7g displayed remarkable antibiofilm activity with an MBIC50 value of 0.02 μg mL-1, which is 50 times lower than ciprofloxacin (MBIC50 = 1.06 μg mL-1). A time-kill kinetics study indicated that 7g showed both concentration and time-dependent bactericidal properties. In addition, 7g effectively inhibited DNA-gyrase supercoiling activity at 1 μg mL-1 (8× MIC). Two compounds 7b and 7d exhibited the highest activity against Mtb with a MIC of 0.5 μg mL-1, while 7c showed the highest activity against P. aeruginosa with a MIC value of 2 μg mL-1. Molecular docking studies revealed that 7g formed stable interactions at the DNA active site.

Design, synthesis, and biological evaluation of evodiamine-indolequinone hybrids as novel NQO1 agonists against non-small cell lung cancer

NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates, which plays an important role in the treatment of non-small cell lung cancer (NSCLC). Based on the indolequinone structure from 5-methoxy-2-methylindole, the indolequinone of NQO1 agonists was first coupled with amino-evodiamine derivatives by esterification reaction, and sixteen new compounds targeting NQO1 were developed. Among them, compounds 11b and 12d (IC50 = 2.72 or 3.66 µM, respectively) were showed better activity by cytotoxicity assay than the reference drug EVO (IC50 = 19.65 µM). Furthermore, the results of flow cytometry analysis showed that compounds 11b and 12d promoted apoptosis in A549 cells, blocked the cell cycle to the G2/M stage and caused a burst of reactive oxygen species. Western blotting experiments revealed that compounds 11b and 12d, after 24 h of treatment in A549 cells, downregulate the expression of Keap1 while upregulating the expression of Nrf2, NQO1, and HO-1. This suggests that compounds 11b and 12d increase cellular antioxidant capacity by regulating the Keap1/Nrf2/NQO1 antioxidant pathway. In vivo anti-tumor experiments showed that the reference drugs EVO (TGI = 15.94 %) and 5-Fu (TGI = 27.54 %) inhibited the proliferation of tumor tissue, while compound 11b could better inhibit the proliferation of tumor tissue (TGI = 39.13 %). In conclusion, our research results suggest that compounds 11b and 12d are potent agonism of the NQO1 signaling pathway and provide a potential opportunity to improve the treatment of NSCLC.

Synthesis, Characterization, and Molecular Modeling Studies of Novel Indenopyridazine-thiazole Molecular Hybrids

Background: Previous studies have reported various biological activities of indeno-pyridazine and thiazole derivatives, including antiviral activity and CoV-19 inhibition. In this paper, the authors aimed to design, synthesize, and characterize a novel series of indenopyridazinethiazoles, starting with 2-(4-cyano-3-oxo-2,3-dihydro-9H-indeno[2,1-c]pyridazin-9-ylidene)-hydrazine-1-car-bothioamide and available laboratory reagents. Methods: The strategy involved the synthesis of indeno[2,1-c]pyridazincarbothioamide, followed by its reaction with various hydrazonoyl chlorides and α-halocompounds (phenacyl bromides and α-chloroketones) to obtain the desired indenopyridazinethiazole derivatives. The synthesized structures were confirmed using IR, NMR, mass spectra, elemental analysis, and alternative synthesis when possible. Docking scores and poses of thirteen synthesized compounds were examined using Auto-Dock4.2.6 software against multiple targets of SARS-CoV-2, including 3C-like protease (3CLpro), helicase, receptor binding domain (RBD), papain-like protease (PLpro), neuropilin-1 (NRP-1), RNA-dependent RNA polymerase (RdRp), and human angiotensin‐converting enzyme 2 (ACE2). Results: Docking predictions revealed that compound 13d exhibited high potency against 3CLpro and helicase, with docking scores of -10.9 and -10.5 kcal/mol, respectively. Compound 10c showed su-perior docking scores against RBD and ACE2, with values of -8.7 and -11.8 kcal/mol, respectively. Compounds 10a, 13c, and 7b demonstrated excellent docking scores against RdRp, PLpro, and NRP-1, with values of -10.3, -10.4, and -8.6 kcal/mol, respectively. Conclusion: The authors recommend further experimental assessments of compounds 13d, 10c, 10a, 13c, and 7b against SARS-CoV-2 multi-targets, considering their promising docking scores.

Novel potent SOS1 inhibitors containing a tricyclic quinazoline scaffold: A joint view of experiments and simulations.

Small molecules that possess the ability to regulate the interactions between Son of Sevenless 1 (SOS1) and Kristen rat sarcoma (KRAS) offer immense potential in the realm of cancer therapy. In this study, we present a novel series of SOS1 inhibitors featuring a tricyclic quinazoline scaffold. Notably, we have identified compound 8d, which demonstrates the highest potency with an IC50 value of 5.1nM for disrupting the KRAS:SOS1 interaction. Compound 8d exhibits a promising pharmacokinetic profile and achieves a remarkable 70.5% inhibition of tumor growth in pancreas tumor xenograft models. Furthermore, molecular dynamic simulations have unveiled that the tricyclic quinazoline derivatives exhibit extensive interaction with Tyr884, a crucial residue for the recognition between SOS1 and KRAS. Our findings provide fresh insights into the design of future SOS1 inhibitors, paving the way for innovative therapeutic strategies.

Facile synthesis of functionalized quinolinones in a green reaction medium and their photophysical properties.

A facile and green chemical approach was successfully developed to construct functionalized quinolinones utilizing substituted alcohols, alkyl acetoacetate, and α-bromo ketones. Various quinolinones bearing either electron-rich or electron-deficient groups at different positions were synthesized in moderate to good yields under mild reaction conditions. The plausible mechanistic pathway for this transformation is supported by experimental evidence and control experiments. This simple approach for synthesizing quinolinones could open new avenues for discovering novel biological and pharmaceutical compounds. The use of affordable nickel catalysts, mild reaction conditions, operational simplicity, and high atom economy are attractive features of this method. Furthermore, the synthetic efficiency has been demonstrated through gram-scale experiments. Our research also provides valuable insights into the photophysical properties of the synthesized derivatives. Notably, compound 6n exhibited the highest Stokes shift (216 nm) in DCM solvent. Furthermore, compounds 5d and 6j showed positive solvatochromism, displaying a stronger emission as the solvent polarity increased. Additionally, compound 6j displayed aggregation-induced emission (AIE) properties in a DMSO : water mixture, making it suitable for use as a security ink, highlighting its potential applications in various fields.

Basic pharmacological evaluation of modified phenyl carbamic acid derivatives on cardiovascular functions under in vitro conditions in rats.

The study aimed to evaluate the basic pharmacological effects of modified phenyl carbamic acid derivates with a basic part made of N-phenylpiperazine (compounds 6a, 6b, 6c, 6d) in Wistar rats. The compounds were evaluated for their ability to decrease the phenylephrine-induced contraction of the aortic strips of rats after repeated administration of the compounds and their ability to inhibit the positive chronotropic effect of isoproterenol on spontaneously beating rat atria. The ability to inhibit the vasoconstriction effect of phenylephrine was confirmed in all compounds in the range from 10.39 % to 13.65 %. The most significant vasoconstriction was achieved in compound 6d (86.35%, p < 0.001). None of the compounds reached the effect of carvedilol. All compounds proved an antagonistic ability to the positive chronotropic effect of isoproterenol. The highest value of the anti-isoproterenol effect was identified for the compound 6c (pA2 = 8.21 ± 0.56; p < 0.05). Only compound 6a decreased heart rate significantly (by 3.17%, p < 0.05), so we can indicate its potential negative chronotropic effect. The obtained results showed that the evaluated compounds confirmed the basic characteristics of beta-blockers with additional α-adrenolytic properties.

Synthesis, Biological Screening, and Molecular Docking of Hybrid Pyrazole Scaffolds for Antitubercular and Antimicrobial Activity

AbstractThis study reports the synthesis, characterization, and docking analysis of 21 novel compounds, including asymmetric dihydropyridines (4a–4o) and chalcones (6a–6f), derived from coupling 1,3‐(substituted)‐diphenyl‐1H‐pyrazole‐4‐carbaldehyde with active methylene compounds and 3‐acetyl‐4‐hydroxycoumarin, respectively. Structural confirmation was achieved through 1H and 13C NMR, IR, and mass spectrometry. Biological screening against mycobacterium tuberculosis H37Ra identified compounds 4b, 4d, 4f, 4g , 4i, 4k, 6e, and 6f as significant antitubercular agents. Antibacterial evaluation at 30 µg/mL showed selective inhibition of gram‐positive bacteria, with compound 6e active against Staphylococcus aureus and Bacillus subtilis, and 6f showing activity specifically against S. aureus. Docking studies indicated effective InhA binding (ΔG = −3.52 to −7.27 kcal/mol) and inhibition constants ranging from 2640 to 4.71 µM. Key binding interactions with residues TYR156 and ILE192 were observed, enhancing affinity, particularly for compound 6e. The SAR analysis emphasized the enhanced antitubercular potency of 2‐chloroacetyl and 2,4‐dichlorobenzoyl substitutions in the dihydropyridine series, while in the chalcone series, specific substitutions, such as the 3‐nitro substitution in 6e, enhance antitubercular and antimicrobial potency due to stronger hydrogen bonding and increased polar surface area, while the 4‐fluoro substitution in 6f confers selective activity against S. aureus.

Trolox derivatives: Synthesis, structure-activity relationship and promote wound healing by regulating oxidative stress and inflammation.

To find new antioxidants, 13 Trolox amides (2a-2m) and 7 Trolox esters (3a-3g) were synthesized and evaluated for their anti-inflammatory and antioxidant activity. Compounds 2e, 2i, 3b and 3d showed potent anti-inflammatory and antioxidant activity, amongst them, 3d demonstrated the most photoprotective effects on UVB-irradiated human skin keratinocyte (HaCaT) cells (IC50=5.13µM) through efficiently scavenging free radicals and dose-dependently reducing reactive oxygen species (ROS) and apoptosis generation, as well as effectively promoting wound healing. 3d protected HaCaT cells against oxidative stress, inflammation and cellular damage by the activation of Nrf2/HO-1 signaling and inhibition of NF-κB pathway, further significantly improving wound healing. In acute UVB-induced skin injury mouse model, 3d significantly reduced the level of pro-inflammatory factors, improved the effect of UVB radiation on the activity of antioxidant enzymes, and maintained normal metabolic capacity. In conclusion, 3d may be a potential candidate for developing cosmetics with UVB protective effect.

Synthesis, characterization, and biological profiling of novel benzotriazole-thio linked derivatives as promising anti-inflammatory, analgesic, and antibacterial agents

A series of new compounds, Substituted 2-((2H-benzo[d][1,2,3]triazol-2-yl)thio)-N'-(2-oxoindolin-3-ylidene)acetohydrazide (3a-3g), 2-((2H-benzo[d][1,2,3]triazol-2-yl)thio)-N-(2,4'-dioxospiro[indoline-3,2'-thiazolidin]-3'yl)acetamide (4a-4g), and 2'-(((2H-benzo[d][1,2,3]triazol-2-yl)thio)methyl)spiro[indoline-3,5'-thiazolo[4,3-b][1,3,4]oxadiazol]-2-one (5a-5g), were synthesized and checked for their anti-inflammatory, analgesic, and antibacterial activities. Compound 5d proved to be the most potent anti-inflammatory and antibacterial agent. The analgesic activity, however, was maximum in compound 5e. The structural integrity of the synthesized compounds was ascertained using elemental analysis, infrared spectroscopy (IR), and proton nuclear magnetic resonance spectroscopy (¹H NMR).

Design, synthesis, and structural investigations of novel (S)-amide derivatives as promising ACE inhibitors

Novel derivatives of potential angiotensin converting enzyme (ACE-I) inhibitors (compounds 5a-e) were synthesized by reacting homophthalic anhydride with methyl esters of L-amino acids (L-isoleucine, L-phenylalanine, L-tyrosine, L-methionine, and L-serine). This reaction resulted in yields of 85% for compound 5a, 83% for compound 5b, 84% for compound 5c, 80% for compound 5d, and 85% for compound 5e. All the synthesized compounds were characterized by 1D and 2D NMR methods. In silico ADME properties of compounds 5a-e conform to Lipinski’s drug rules. The in silico toxicological determination of the synthesized compounds suggest that compound 5a exhibits significant potential for adverse effects, such as causing hormonal imbalances. In comparison, the remaining compounds 5b-c demonstrate a lower risk profile. In silico biological activities of compounds 5a-e in the active site of ACE-I were determined by docking, which were then compared to the FDA approved antihypertensive drugs enalalapril and lisinopril. Docking studies revealed that compound 5b (ΔGcomp = −8.851 kcal/mol) possesses the greatest binding affinity in the Zn2+ binding site of ACE-I compared to those of lisinoprilat (ΔGcomp = −8.066 kcal/mol) and enalapril (ΔGcomp = −7.187 kcal/mol), strongly suggesting a great potential to be a lead candidate for novel antihypertensive drug development.

Green synthesis of hydrazono-thiazolones using vitamin B1 and their antibacterial implications

ABSTRACT The study focuses on green methodologies in synthetic organic chemistry, emphasizing the use of thiamine hydrochloride (Vitamin B1) as an eco-friendly catalyst for synthesizing hydrazono-thiazolones. These compounds serve as versatile core units with various therapeutic activities, including anti-HIV, anti-tubercular, antifungal, antiviral, and anticancer properties. Building on prior research involving sustainable barium oxide-chitosan nanocomposite catalysts, this novel green synthetic approach contributes to the sustainable synthesis of bioactive heterocycles. The synthesized compounds 6a-l were tested in vitro against different bacterial species, revealing notable activity against Gram-positive and Gram-negative bacteria. The MIC investigation showed that compounds 6d, 6e, 6j, and 6k have broad-spectrum antibacterial potential, with 6j and 6k being especially effective, their MICs near those of ciprofloxacin, highlighting their strong antibacterial capabilities. Molecular docking studies predicting the binding mode of the most potent substances to Escherichia coli DNA gyrase (PDB ID 4DUH) aligned well with in vitro studies, confirming the new ligands’ potency as potential antimicrobial agents. In silico investigations for the most potent substances revealed a favorable ADME profile, suggesting promising pharmacological properties. This research contributes to both sustainable synthesis and potential therapeutic applications of hydrazono- thiazolone derivatives.