Compounds 4j Research Articles

Explorations of Agonist Selectivity for the α9* nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation.

There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. This study introduces novel compounds targeting the α9 nicotinic acetylcholine receptor (nAChR) subunit, which is crucial for pain regulation, inflammation, and inner ear functions. Specifically, it identifies novel substituted carbamoyl/amido/heteroaryl dialkylpiperazinium iodides as potent agonists selective for human α9 and α9α10 over α7 nAChRs, particularly compounds 3f, 3h, and 3j. Compound 3h (GAT2711) demonstrated a 230 nM potency as a full agonist at α9 nAChRs, being 340-fold selective over α7. Compound 3c was 10-fold selective for α9α10 over α9 nAChR. Compounds 2, 3f, and 3h inhibited ATP-induced interleukin-1β release in THP-1 cells. The analgesic activity of 3h was fully retained in α7 knockout mice, suggesting that analgesic effects were potentially mediated through α9* nAChRs. Our findings provide a blueprint for developing α9*-specific therapeutics for pain.

Design and synthesis of new dihydropyrimidine/sulphonamide hybrids as promising anti-inflammatory agents via dual mPGES-1/5-LOX inhibition.

A novel series of dihydropyrimidine/sulphonamide hybrids 3a-j with anti-inflammatory properties have been developed and tested as dual mPGES-1/5-LOX inhibitors. In vitro assay, results showed that compounds 3c, 3e, 3h, and 3j were the most effective dual inhibitors of mPGES-1 and 5-LOX activities. Compound 3j was the most potent dual inhibitor with IC50 values of 0.92µM and 1.98µM, respectively. In vivo, anti-inflammatory studies demonstrated that compounds 3c, 3e, 3h, and 3e had considerable anti-inflammatory activity, with EI% ranging from 29% to 71%. Compounds 3e and 3j were equivalent to celecoxib after the first hour but exhibited stronger anti-inflammatory effects than celecoxib after the third and fifth hours. Moreover, compounds 3e and 3j significantly reduced the levels of pro-inflammatory cytokines (PGE2, TNF-α, and IL-6) with gastrointestinal safety profiles. Molecular docking simulations explored the most potent derivatives' binding affinities and interaction patterns within mPGES-1 and 5-LOX active sites. This study disclosed that compound 3j is a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that deserves further preclinical investigation.

In-vitro and in-silico investigations of SLC-0111 hydrazinyl analogs as human carbonic anhydrase I, II, IX, and XII inhibitors.

Two novel series of hydrazinyl-based benzenesulfonamides 9a-j and 10a-j were designed and synthesized using SLC-0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off-target isozyme hCA I. Notably, derivative 10a exhibited superior potency (Ki of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with Kis in the low nanomolar range of 20.5-176.6 nM and 6.0-127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with Ki of 20.5 nM and SI of 200.1, and Ki of 6.0 nM and SI of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Kis = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC-0111 (Kis = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off-target hCA I and II.

Highly Efficient Bimetallic Catalyst for the Synthesis of N-substituted Decahydroacridine-1,8-diones and Xanthene-1,8-diones: Evaluation of their Biological Activity

Background: Bimetallic catalysis plays a major role in boosting the catalytic performance of monometallic counterparts due to the synergetic effect. Method and Materials: In the present study, we have exploited ZrCl4:Mg(ClO4)2 as an efficient bimetallic catalyst for the synthesis of a few biologically relevant N-substituted decahydroacridine-1,8-diones and xanthene-1,8-diones under solvent-free conditions. The complete characterization data (XRD, SEM, BET, pH, TGA, and IR) of the bimetallic catalyst, ZrCl4: Mg(ClO4)2, are provided in the supporting information. Results: Among the compounds screened for anti-oxidant and anti-microbial activities, the acridine derivatives with chloro and fluoro substitutions (compounds 4b, 4c, 4d, and 4j) have exhibited potent activities when compared to other compounds. Among the xanthene derivatives screened for anti-oxidant activity, compounds 5c, 5i, and 5j with chloro and nitro derivatives exhibited potent antioxidant activity, and the rest all showed moderately potent activity. Conclusion: Among the compounds screened for antibacterial activity, compound 5j with chloro substitution showed potent activity, followed by compounds 5c, 5d, 5h, and 5i against Gram +ve bacteria, and compounds 5h, 5f, and 5g with N,N-dimethyl, methoxy and hydroxy substitutions have shown potent activity against Gram -ve bacteria.

Synthesis, characterization, antimicrobial and antioxidant activity of 2- (2′-hydroxyphenyl) -1,3,4-oxadiazolyl-5-amino acid derivatives

The synthesis and biological assessment of 2,5-disubstituted-1,3,4-oxadiazoles derivatives from amino acids as new potential antibacterial and antioxidant agents have been reported. The structures of the new synthesized compounds were characterized based on physicochemical and spectral data UV–Visible, IR, 1HNMR, 13CNMR. All the target compounds were screened for theirin vitroantibacterial activityagainst three Gram-positivebacterial strains,namely Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria innocua ATCC 33090, and two Gram-negative bacterial strains,namely Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, andantifungal activityagainst Candida albicans ATCC 10231 in comparison with Amoxicillin, Tetracycline, Gentamicin and Oxacillin. The only compound 1-{(4S)-4-amino-4-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]butyl}guanidine 5e with the amine radical thatshowed excellent results against all bacteria, particularly against L. innocua (IZ = 12 mm), has excellent antifungal activity (IZ = 32 mm). The compounds 2-[5-(1-amino-3-methylbutyl)-1,3,4-oxadiazol-2-yl]phenol 5b and 2-[5-(pyrrolidin-2-yl)-1,3,4-oxadiazol-2-yl]phenol 5j have excellent activities (IZ = 27 and IZ = 28 mm, respectively) against B. cereus and P. aeruginosa. Compounds 2-{5-[(1R)-1-amino-2-sulfanylethyl]-1,3,4-oxadiazol-2-yl}phenol 5c, 2-{5-[(1S)-1-amino-3-(methylsulfanyl)propyl]-1,3,4-oxadiazol-2-yl}phenol 5dwith the sulfur radical, 3--[5-(2-3-amino hydroxyphenyl)-1,3,4-oxadiazol-2-yl]propanamide 5g with the amide radical, 5j with the amino radical, and 4-amino-4-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]butanoic acid 5k gave good results against B. cereus, where 19 mm < IZ < 23 mm. We also found that compound 5j has the greatest activity (IZ = 33 mm) against C. albicans, followed by compounds 5e (IZ = 32 mm) and 5b (IZ = 30 mm). The synthesized compounds were also screened for radical scavenging antioxidant activities by DPPH, FRAP, and TAC assays and found to be good antioxidant agents. According to the IC50 values, all compounds demonstrated good to excellent activity, especially 5b and 2-{5-[1-amino-2-(1H-imidazol-4-yl)ethyl]-1,3,4-oxadiazol-2-yl}phenol 5i for DPPH, 5e and 5i for FRAP and methyl 2-hydroxybenzoate 2,2-{5-[1-amino-2-(1H-indol-3-yl)ethyl]-1,3,4-oxadiazol-2-yl}phenol 5h with the imidazol group and 2-[5-(1,5-diaminopentyl)-1,3,4-oxadiazol-2-yl]phenol 5f with the imidazol group for TAC. All these compounds showed better activity than AA and BHT.

A Potential Multitarget Insect Growth Regulator Candidate: Design, Synthesis, and Biological Activity of Novel Acetamido Derivatives Containing Hexacyclic Pyrazole Carboxamides.

Insect growth regulators (IGRs) are important green insecticides that disrupt normal growth and development in insects to reduce the harm caused by pests to crops. The ecdysone receptor (EcR) and three chitinases OfChtI, OfChtII, and OfChi-h are closely associated with the molting stage of insects. Thus, they are considered promising targets for the development of novel insecticides such as IGRs. Our previous work identified a dual-target compound 6j, which could act simultaneously on both EcR and OfChtI. In the present study, 6j was first found to have inhibitory activities against OfChtII and OfChi-h, too. Subsequently, taking 6j as a lead compound, 19 novel acetamido derivatives were rationally designed and synthesized by introducing an acetamido moiety into the amide bridge based on the flexibility of the binding cavities of 6j with EcR and three chitinases. Then, their insecticidal activities against Plutella xylostella (P. xylostella), Ostrinia furnacalis (O. furnacalis), and Spodoptera frugiperda (S. frugiperda) were carried out. The bioassay results revealed that most of these acetamido derivatives possessed moderate to good larvicidal activities against three lepidopteran pests. Especially, compound I-17 displayed excellent insecticidal activities against P. xylostella (LC50, 93.32 mg/L), O. furnacalis (LC50, 114.79 mg/L), and S. frugiperda (86.1% mortality at 500 mg/L), significantly better than that of 6j. In addition, further protein validation and molecular docking demonstrated that I-17 could act simultaneously on EcR (17.7% binding activity at 8 mg/L), OfChtI (69.2% inhibitory rate at 50 μM), OfChtII (71.5% inhibitory rate at 50 μM), and OfChi-h (73.9% inhibitory rate at 50 μM), indicating that I-17 is a potential lead candidate for novel multitarget IGRs. This work provides a promising starting point for the development of novel types of IGRs as pest management agents.

Synthesis and anti-breast cancer evaluation of fused imidazole-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 of ultrasound, the [3 + 2] cycloaddition followed by CN bond formation reaction between 2-chloro-N-(1-methyl-1H-imidazol-2-yl)acetamide and substituted aryl iodoalkynes was carried out ourpreviously reported condition. The cancer activity of the synthesized compounds were then tested in vitro against two breast cancer cell lines MCF-7 and MDA-MB231 and some of the compounds 5g and 5j showed more potent activity against MCF-7 compared to standard erlotinib (IC50 = 4.70 ± 0.11 μM) with IC50 values 4.02 ± 0.74 and 4.23 ± 0.65 μM. Later, in vitro EGFR results revealed that compound 5g (IC50 = 0.38 ± 0.02 μM) have shown more effective than the conventional medicine erlotinib (IC50 = 0.42 ± 0.04 μM). Compounds 5j (IC50 = 0.42 ± 0.05 μM) have shown equipotent, 5i (IC50 = 0.53 ± 0.02 μM) and 5k (IC50 = 0.58 ± 0.02 μM) were shown good activity compared to the standard erlotinib. In silico investigations of more potent compounds (5g, 5i, 5j, 5k, and 5q) and erlotinib on the EGFR protein indicated that all five compounds had comparable binding energies and inhibition constants than the erlotinib.

5-Oxo-dihydropyranopyran derivatives as anti-proliferative agents; synthesis, biological evaluation, molecular docking, MD simulation, DFT, and in-silico pharmacokinetic studies

A series of ethyl 2-amino-7-methyl-5-oxo-4-phenyl-4,5-dihydropyrano[4,3-b]pyran-3-carboxylate derivatives (4a-j) bearing different substitutions on the C4-phenyl ring was synthesized. The anti-proliferative activity of all the synthesized compounds was assessed against two human cancer-cell lines, including SW-480 and MCF-7, by using MTT method. Derivatives 4g, 4i, and 4j, possessing 4-NO2, 4-Cl, and 3,4,5-(OCH3)3 substitutions, were found to be the most potent compounds against both cell lines. The obtained IC50 values for 4g, 4i, and 4j were 34.6, 35.9, and 38.6 μM against SW-480 cells and 42.6, 34.2, and 26.6 μM against MCF-7 cells, respectively. Evaluation of the free radical scavenging potential of the compounds against DPPH radicals showed the highest result for compound 4j with an EC50 value of 580 μM. Molecular docking studies revealed the compounds were well accommodated within the binding site of cyclin-dependent kinase-2 (CDK2) with binding energies comparable to those of DTQ (the co-crystallized inhibitor) and BMS-265246 (a well-known CDK2 inhibitor). Molecular dynamics simulation studies confirmed the interactions and stability of the 4g-CDK2 complex. All derivatives, except 4g, were predicted to comply with the drug-likeness rules. Compound 4j may be proposed as an anti-cancer lead candidate for further studies due to the promising findings from in-silico pharmacokinetic studies, such as high GI absorption, not being a P-gp substrate, and being a P-gp inhibitor. Density functional theory (DFT) analysis was performed at the B3LYP/6–311++G (d,p) level of theory to examine the reactivity or stability descriptors of 4d, 4g, 4i, and 4j derivatives. The highest value of energy gap between HOMO and LUMO and thermochemical parameters were obtained for 4i and 4j.

Synthesis, biological evaluation, and docking studies of pyrazole-linked benzothiazole hybrids as promising anti-TB agents

Tuberculosis (TB) is a global pandemic killing millions of people every year. Yet, resistant strains make curing TB quite challenging. Herein, a series of new pyrazole-linked benzothiazole hybrids was synthesized and evaluated for their anti-TB activity against three Mycobacterium tuberculosis strains (drug sensitive (DS), multidrug-resistant (MDR) and extensively drug-resistant (XDR)). The substituted 2,5-dimethylphenoxy -, 2,6-dichlorophenoxy -, 2,6-dimethoxyphenoxy -, 4-methylpiperazin-1-yl-,and pyrrolidin-1-ylpyrazole-benzothiazole conjugates (compounds 10j, 10k,10l, 11cand 12 respectively) displayed promising anti-TB activity in comparison to the reference compound isoniazid against the DS strain with (MIC: 1.74–3.68 μM/mL)To further study the mode of action of these anti-TB compounds, their inhibition of the Mycobacterium tuberculosisenoyl-acyl carrier protein reductase enzyme (InhA) was tested. The 3-acetamidophenoxy-, 2,6-dichlorophenoxy -,andpyrrolidin-1-ylpyrazole-benzothiazole conjugates(Compounds 10i, 10j and 12 respectively) showed strong inhibition of InhA in comparison to the reference compound, triclosan, with IC50 values of 6.4–7.9 μM. Moreover, a molecular docking study was carried out to investigate the predicted binding interactions of the synthesized inhA inhibitors in the binding pocket of the inhA enzyme. The calculated docking energies of the developed novel pyrazole-linked benzothiazole hybrids were consistent with their tested anti-tubercular activity.

Insight on novel oxindole conjugates adopting different anti-inflammatory investigations and quantitative evaluation.

Background: A dual COX/5-LOX strategy was adopted to develop new oxindole derivatives with superior anti-inflammatory activity. Methods: Three series of oxindoles - esters 4a-p, 6a-l and imines 7a-o - were synthesized and evaluated for their anti-inflammatory and analgesic activities. Molecular docking and predicted pharmacokinetic parameters were done for the most active compounds. A new LC-MS/MS method was developed and validated for the quantification of 4h in rat plasma. Results: Compounds 4h, 6d, 6f, 6j and 7m revealed % edema inhibition up to 100.00%; also, 4l and 7j showed 100.00% writhing protection. Compound 4h showed dual inhibitory activity with IC50=0.0533 and 0.4195μM for COX-2 and 5-LOX, respectively. Molecular docking rationalized the obtained biological activity. The pharmacokinetic parameters of 4h from rat plasma were obtained.

Novel Schiff base derivatives containing 4,5-disubstituted thiazole as potential antibiofilm, anti-inflammatory and antioxidant agents: Green synthesis, molecular docking and ADME analysis

We report the microwave-assisted (MW) green synthesis of some novel 4,5 disubstituted thiazole-containing Schiff base derivatives (SBs) as antibiofilm, anti-inflammatory, and antioxidant agents. Spectroscopic techniques were used to confirm the formation of synthesized compounds. In-vitro antibiofilm and antifungal activity of synthesized molecules were evaluated against the Candida albicans strain (MTCC 227) by broth dilution method. Among the tested molecules, 3a showed excellent inhibition of both biofilm formation and planktonic growth at much lower MIC50 values (5.56 μg/mL and 1.20 μg/mL respectively) than other derivatives. Moreover, the spot assay of compound 3a showed fungicidal activity (100% cell death) for biofilm formation and planktonic growth at the lowest MFC values (10 μg/mL and 3.12 μg/mL respectively) compared to the standard drug fluconazole. In addition, the biofilm inhibition was further confirmed by morphological study through FESEM analysis. The anti-inflammatory study of SBs by protein denaturation method indicates that compound 3a (63.19%) was the most active anti-inflammatory agent at a lower concentration of 100 μg/mL in the series than the standard ibuprofen (42.36%). Whereas, the antioxidant study of SBs by the DPPH scavenging method shows compound 3j (IC50 = 436.10 μg/mL) was the more potent antioxidant agent as compared to other tested compounds and standard drug ascorbic acid (IC50 = 626.99 μg/mL). Furthermore, the molecular docking study of SBs with the active sites of sterol 14-α demethylase CYP51 enzyme of (PDB:5TZ1) C. albicans shows strong binding properties, supporting the experimental results of inhibition of biofilm formation. Additionally, the ADME characteristic of SBs demonstrates their potential for development as oral medication candidates.

A novel Cu(II) nanoparticles anchored on cyanuric chloride-attached magnetic nanocatalyst: A highly stable, recyclable and efficient nanocatalyst for the synthesis of chromene derivatives

As a novel core-shell magnetic nanocatalyst, a copper nanocatalyst, Cu(II)-Schiff base-TCT-APTES@SiO2@Fe3O4 was successfully synthesized through the reaction of the cyanuric chloride grafted onto the core-shell magnetic nanocatalyst with Schiff base complex and finally treated with Cu(NO3)2·3H2O. The noteworthy point is that the novel Schiff base separated by employing hydrazine with 2-pyridinecarboxaldehyde was synthesized and purified by a simple washing and identified by FT-IR, 1H NMR and 13C NMR spectrums. The catalyst was studied relying on various techniques and spectroscopic procedures including FT-IR, SEM, TEM, XPS, XRD, VSM, BET, TGA, and ICP analyses. The TEM images indicated that the catalyst was synthesized with an average size of 37–47 nm and a spherical shape. BET analysis showed that our catalyst has been synthesized with mesoporous structure and high surface area (52.55 m2/g). Moreover, the XPS results clearly demonstrated the peak at 937.2 eV and 949.2 eV that was related to the presence of Cu(II) in structure of catalyst. Then, copper nanocatalyst was successfully tested for the one-pot three component reaction of chromene derivatives of various aldehydes, phenols (2-hydroxynaphthalene-1,4-dione, resorcinol and β-naphthol) and malononitrile in ethanol under reflux conditions. All products were obtained in excellent yields for a diverse range of aromatic aldehydes. TON and TOF numbers for the compound 4j with the highest yield were found to be 192 and 581.8 h−1, respectively. Further, the copper catalyst can be reused by external magnetic field over seven times with a negligible loss in activity, showing 0.08% leaching of Cu after 7 times recycling. Also, Density Functional Theory (DFT) calculations were carried out to investigate the electrostatic potential (ESP), natural bond orbital (NBO), images of HOMO and LUMO orbitals and drawing the reaction mechanism using total energy of reactant and product.

Synthesis of 8-methyl-2-phenylquinazolin-4(3H)-ones derived Schiff's bases: Spectroscopic properties, SAR, docking approaches and their anticancer and antimicrobial activity

A series of new compounds based on 8-methyl-2-phenyl quinazolinone Schiff's base were synthesized from 3-amino quinazolinone intermediates. These compounds were evaluated for their potential as anticancer and antimicrobial agents through docking analysis. Anticancer evaluation was done against sixty different cancer cell lines. Compounds 7b and 7 h showed strong efficacy against Melanoma (MDA-MB-435 Cell lines) and Non-Small Cell Lung Cancer (NCI-H522), respectively. Compound 7 g was found to be predominantly effective against both breast cancer (HS-578T) and central nervous system cancer (SNB-19). The antimicrobial activity results showed that the newly synthesized compounds 7d and 7j, which contain halogen, exhibited potential inhibiting action against selected bacterial and fungal microorganisms. The SAR study revealed that compounds with EDGs like hydroxyl and meta-substituted chloro group were found to be more potent in anticancer studies; while compounds with EWGs substituted in the para position (7d and 7j) demonstrated higher antimicrobial activity. Moreover, Antimicrobial docking analysis indicated that compounds 7d and 7j have a high affinity towards molecular targets found in both bacteria and fungi, with negative binding energies ranging from -8 to -12.5 kcal/mol. We endorse further evaluation of these compounds in combination with standard antibiotics to potentially increase their synergistic effect.

One-step synthesis of diaryloxadiazoles as potent inhibitors of BCRP.

Aim: BCRP plays a major role in the efflux of cytotoxic molecules, limiting their antiproliferative activity. We aimed to design and synthesize new BCRP inhibitors to render cancerous tumors more sensitive toward anticancer agents. Materials & methods: Based on our previous work, we conceived potential BCRP inhibitors derived from 1,3,4-oxadiazoles bearing two substituted phenyl rings. Results: Evaluating 19 derivatives, we found that 2,5-diaryl-1,3,4-oxadiazoles possessing methoxy groups were the most active. The highest activity was recorded with derivatives bearing three methoxy groups. The most active compound (3j) was selective in inhibiting BCRP and nontoxic as evidenced by cellular tests. Conclusion: 3j is a promising BCRP inhibitor thanks to its synthetic accessibility and biological profile.

Design, synthesis, and mechanistic evaluation of novel benzimidazole-hydrazone compounds as dual inhibitors of EGFR and HER2: Promising candidates for anticancer therapy

A series of twelve benzimidazole-hydrazone compounds were synthesized and evaluated for their cytotoxicity on three cancer cell lines (HepG-2, MCF-7, and HCT-116) using the MTT assay. The compounds' IC50 values were compared to the anticancer drug sunitinib. Additionally, we investigated the dual inhibition of compounds 6e and 6j on EGFR and HER2 tyrosine kinase enzymes. Flow cytometry analysis revealed that compound 6e induced cell cycle arrest and apoptosis in HepG-2 cells. Molecular docking analysis showed that compound 6e interacted with the ATP binding pocket of EGFR and HER2, exhibiting hydrophobic interactions and distinct hydrogen bonding patterns. Notably, compounds 6e, 6g, 6h, 6j, and 6l exhibited potent cytotoxicity comparable to sunitinib against all tested cancer cell lines. Compound 6e demonstrated dual inhibition of EGFR and HER2 and displayed favorable druglike properties. These findings suggest that compound 6e has potential as a lead compound for targeting the EGFR and HER2 pathways and warrant further optimization and development as a potential anticancer therapeutic agent.

Dimeric peptoids as antibacterial agents

Building upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal interplay between hydrophobicity and cationicity in optimizing efficacy against specific bacteria. The bromophenyl dimeric guanidinium peptoid compound 10j showed excellent activity against S. aureus 38 and E. coli K12 with MIC of 0.8 μg mL−1 and 6.2 μg mL−1, respectively. Further investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes, as suggested by tethered bilayer lipid membranes (tBLMs) and cytoplasmic membrane permeability studies. Notably, these promising antibacterial agents exhibited negligible toxicity against mammalian red blood cells. Additionally, the study explored the potential of 12 active compounds to disrupt established biofilms of S. aureus 38. The most effective biofilm disruptors were ethyl and octyl-naphthyl guanidinium peptoids (10c and 10 k). These compounds 10c and 10 k disrupted the established biofilms of S. aureus 38 with 51 % at 4x MIC (MIC = 17.6 μg mL−1 and 11.2 μg mL−1) and 56 %-58 % at 8x MIC (MIC = 35.2 μg mL−1 and 22.4 μg mL−1) respectively. Overall, this research contributes insights into the design principles of cationic dimeric peptoids and their antibacterial activity, with implications for the development of new antibacterial compounds.

Design, synthesis and characterization of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate as anti-tubercular agents: In silico screening for possible target identification.

A thorough search for the development of innovative drugs to treat tuberculosis, especially considering the urgent need to address developing drug resistance, we report here a synthetic series of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o) as potent anti-tubercular agents. These morpholino-indolizines were synthesized by reacting 4-morpholino pyridinium salts, with various electron-deficient acetylenes to afford the ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o). All synthesized intermediate and final compounds are characterized by spectroscopic methods such as 1H NMR, 13C NMR and HRMS and further examined for their anti-tubercular activity against the M. tuberculosis H37Rv strain (ATCC 27294-American type cell culture). All the compounds screened for anti-tubercular activity in the range of 6.25-50 μM against the H37Rv strain of Mycobacterium tuberculosis. Compound 5g showed prominent activity with MIC99 2.55 μg/mL whereas compounds 5d and 5j showed activity with MIC99 18.91 μg/mL and 25.07 μg/mL, respectively. In silico analysis of these compounds revealed drug-likeness. Additionally, the molecular target identification for Malate synthase (PDB 5CBB) is attained by computational approach. The compound 5g with a MIC99 value of 2.55 μg/mL against M. tuberculosis H37Rv emerged as the most promising anti-TB drug and in silico investigations suggest Malate synthase (5CBB) might be the compound's possible target.

Molecular Docking, Toxicity Study and Antimicrobial Assessment of Novel Synthesized 1,3-(Disubstituted)-thiazol-2-amines

In current study, a novel analogous of substituted-2-aminothiazoles (3a-o) were synthesized through a multi-step synthetic process. Structural elucidation of these newly synthesized substituted-2-aminothiazoles were achieved using combination of analytical techniques, comprising proton nuclear magnetic resonance (PNMR), mass spectrometry and FTIR. An in vitro investigation was performed to measure the efficacy of antibacterial and antimycotic characteristics of these novel compounds (3a-o). Specifically, the growth-inhibiting action against the test fungal strains, including A. niger, M. purpureos and A. flavus was examined. Additionally, their inhibitory antibacterial activity against key bacterial strains, including P. aeruginosa, S. aureus and E. coli was ascertained employing the agar diffusion technique. The results of antibacterial screening disclosed that maximum number of the thiazole derivatives viz. 3a, 3d, 3e, 3i, 3k, 3l and 3n displayed minimum inhibitory concentration of 12.5 µg/mL for E. coli. While compounds 3k and 3n displayed minimum inhibitory concentration of 12.5 µg/mL for S. aureus. A minimum inhibitory concentration of 25 µg/mL was exhibited by compounds 3i, 3l and 3n against P. aeruginosa. None of the 2-aminothiazole derivative disclosed promising action against the fungal strains. Screening for in silico ADME and toxicity studies revealed that compounds are fairly compatible and were devoid of potential toxicity except compounds 3j and 3m. The docking studies on DNA gyrase (PDB ID; 1KZN) shows favourable binding interaction comparable to the pre-occupied ligand clorobiocin.

Synthesis, Anticancer Evaluation and Molecular Docking Studies of 1-(2-Fluorobenzyl)piperazine Triazoles: A Novel Breast Cancer Cell Inhibitors

New series of 1-(2-fluorobenzyl)piperazine triazoles 7(a-k) have been synthesized and evaluated for anticancer activity. The molecular structures of all the compounds were established by employing 1H NMR, 13C NMR and mass spectral analysis. In vitro anticancer activity was evaluated using MTT assay against MCF7 breast cancer cell line. Compounds 7i and 7j bearing 4-fluorophenyl and 2-fluorophenyl pendant from triazole substituent phenyl ring exhibited the highest anticancer efficacy with IC50 values of 12.09 µg/mL and 15.12 µg/mL, respectively. A molecular docking study conducted on human HER2 complexed with hercepatin fab was acquired from Protein Data Bank (PDB ID: 1N8Z). Molecular docking studies demonstrated Leu443, Gly442 and Leu27 as key residues interacting with active compounds.

Benzohydrazide as a good precursor for the synthesis of novel bioactive and anti-oxidant 2-phenyl-1,3,4-oxadiazol-aminoacid derivatives: Structural determination, biological and anti-oxidant activity

The synthesis and biological assessment of 2,5-disubstituted-1,3,4-oxadiazole derivatives from benzo hydrazide and amino acids as novel potential antioxidant and antibacterial agents have been reported. The structures of the new compounds were characterized by physicochemical properties and spectral methods. The synthesized compounds were screened for their in vitro antibacterial activity against three Gram-positive bacterial strains, namely Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria innocua ATCC 33090, and two Gram-negative bacterial strains, namely Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, and antifungal activity against Candida albicans ATCC 10231 in comparison with Amoxicillin, Tetracycline, Gentamicin and Oxacillin as standards. Most of the compounds have excellent efficacy, and some of them, such as 5i, 5g, 5d, 5c, and 5j can inhibit their activity better or very close to that of Amoxicillin, Tetracycline, Gentamicin, Oxacillin used as standards. Compounds 5b and 5i provided good results against L. innocua with inhibition values of IZ = 14 mm and IZ = 22 mm, respectively, while the rest of the compounds and antibiotics were unable to inhibit it. Compounds 5c, 5d, 5g and 5j showed excellent activity against C. albicans with values between 31 mm and 34 mm. These results were better than all the standards used. The MIC value (25 µg/ml) for derivatives 5(c-e), 5g and 5(i-j) against B. cereus represent the best activity of the tested compounds. All the target compounds were also screened for radical scavenging antioxidant activities by DPPH, FRAP, and TAC assays and found to be excellent antioxidant agents. According to the results, it was observed that most derivatives synthesized showed excellent activity with a concentration of 250 µg/ml as an antioxidant agent (76 % < RSA < 95.5 %) which gave an inhibition percentage that was better or very close to that of ascorbic acid and better than BHT.