Stereoselective synthesis and <i>in-silico</i> evaluation of C4-benzimidazolyloxyphenyl substituted <i>trans</i>-β-lactam derivatives as promising novel PPARγ activators

Bhalla, Jitender; Bari, S. S.; Chaudhary, Ganga Ram; Kumar, Ashok; Rathee, Aditi; Sharma, Radhika; Bhalla, Aman

doi:10.1080/00397911.2021.1992441

Cited by 7 publications

(3 citation statements)

References 25 publications

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“…When compared to the C3 functionality of the β-lactam unit, the docking analysis demonstrated that N1 functionality has a significant impact on the binding affinity of the molecules. Furthermore, β-lactam 24a with a paramethoxyphenyl group at N1 shows promise for future anti-diabetic drug development ( Figure 27 ) [ 99 ].…”

Section: Recent Developments In the Medicinal Chemistry Of Pparsmentioning

confidence: 99%

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

et al. 2022

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The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the activation of PPARγ brings about insulin sensitization and increases the metabolism of glucose. On the other hand, PPARβ when activated increases the metabolism of fatty acids. Further, these PPARs have been claimed to be utilized in various metabolic, neurological, and inflammatory diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. A series of different heterocyclic scaffolds have been synthesized and evaluated for their ability to act as PPAR agonists. This review is a compilation of efforts on the part of medicinal chemists around the world to find novel compounds that may act as PPAR ligands along with patents in regards to PPAR ligands. The structure–activity relationship, as well as docking studies, have been documented to better understand the mechanistic investigations of various compounds, which will eventually aid in the design and development of new PPAR ligands. From the results of the structural activity relationship through the pharmacological and in silico evaluation the potency of heterocycles as PPAR ligands can be described in terms of their hydrogen bonding, hydrophobic interactions, and other interactions with PPAR.

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Section: Recent Developments In the Medicinal Chemistry Of Pparsmentioning

confidence: 99%

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

et al. 2022

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“…[33][34][35] Our previous studies have been dedicated towards the synthesis of aryl/pyrazolyl substituted spirocyclic and pyrazolo[5,1b]thiazole-3-carboxylate/(4-thiophenyl)pyrazolyl/benzimidazolyloxyphenyl conjugated heterocyclic β-lactams. [36][37][38][39] Moreover, the advancement in spirocyclic systems and charismatic contour of thiophene analogs in discovering new pharmaceutically active compounds, encouraged us to design spiro-hybrid heterocyclic building blocks with improved pharmacokinetics and safety profile. By blending various aliphatic and heterocyclic elements, we crafted a focused collection of pioneering spirocyclic-β-lactams poised as potential antimicrobial candidates.…”

Section: Introductionmentioning

confidence: 99%

“…Unsubstituted or multi‐substituted thiophene ring behaves as structural stone in diverse drug derivatives which might be assigned to its consequential pharmacokinetic significance [33–35] . Our previous studies have been dedicated towards the synthesis of aryl/pyrazolyl substituted spirocyclic and pyrazolo[5,1‐ b ]thiazole‐3‐carboxylate/(4‐thiophenyl)pyrazolyl/benzimidazolyloxyphenyl conjugated heterocyclic β‐lactams [36–39] . Moreover, the advancement in spirocyclic systems and charismatic contour of thiophene analogs in discovering new pharmaceutically active compounds, encouraged us to design spiro‐hybrid heterocyclic building blocks with improved pharmacokinetics and safety profile.…”

Section: Introductionmentioning

confidence: 99%

C7‐Halomethylene/methyl‐C3‐thiophenyl‐spirocyclic‐β‐lactams: Synthesis, X‐ray Analysis, Antimicrobial Evaluation, Cytotoxicity Profile and Molecular Docking Interactions

Yadav,

Kumari,

Kaur

et al. 2023

ChemMedChem

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In the realm of healthcare, the continuous evolution of new alternative antimicrobial agents provides hope in addressing the progressively daunting issue of severe multidrug resistance. In our quest to confront drug resistance, we explored the conjugation of thiophene motif with β‐lactams into single matrix to develop a series of spirocyclic‐β‐lactams. For this, stereoselective synthesis of cis‐C3‐alkyloxy‐C4‐thiophenyl substituted monocyclic β‐lactams was achieved which were further subjected to intramolecular sulfenyl‐cyclization to furnish C7‐halomethylene/methyl‐C3‐thiophenyl substituted spirocyclic‐β‐lactams. The synthesized compounds were investigated in vitro for their potential activity against six multidrug‐resistant bacterial strains. The most promising C7‐iodomethylene‐C3‐thiophenyl‐spirocyclic‐β‐lactam 7 a appended with 4′‐methoxyphenyl moiety, exhibited acceptable activity against B. cereus and P. aeruginosa with MIC values of 0.75 and 6.25 μg/mL respectively, surpassing ampicillin and vancomycin. Furthermore, this compound demonstrated antifungal effectiveness against C. tropicalis (1.5 μg/mL). On the basis of substituent type and their respective positions, compounds possessing −OCH3 and −C=CHX (halomethylene) groups exhibited more inhibitory potential than others. Active derivatives tested for their cytotoxicity on normal human hepatic (THLE‐2) cell lines confirmed their non‐toxic nature. Further, molecular docking studies predicted the favourable binding interactions of spirocycles within active sites of target proteins. Moreover, several compounds illustrate satisfactory in silico ADME profile. These outcomes provided bright prospect for development of spirocyclic‐β‐lactams as potential solution to combat evolving multidrug resistance.

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Design, Synthesis and Biological Evaluation of C3‐Indolyl/(3‐chloro‐indolyl)‐C4‐aryl/heteroaryl‐azetidin‐2‐ones

Yadav,

Fatimah,

Sahoo

et al. 2024

ChemMedChem

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Herein, trans‐ and cis‐azetidin‐2‐ones 3‐6 were strategically synthesized, capitalizing on the bioactivity of azetidin‐2‐ones and indole pharmacophore, followed by a comprehensive characterization using a diverse array of spectroscopic techniques. The sixteen azetidin‐2‐ones were examined for antimicrobial activities against both Gram‐negative (P. aeruginosa, E. coli, A. baumannii) and Gram‐positive bacteria (S. aureus, E. faecium, B. cereus), as well as against C. albicans and C. tropicalis fungal strains. The highly potent compounds (5a, 6b, 6d) demonstrated maximum inhibition against all multidrug‐resistant strains, with minimum inhibitory concentrations ranging from 0.97‐3.9 μg/mL, surpassing the potency of standard ampicillin (MIC: 3.12‐50 μg/mL). Moreover, 6b and 6d exhibited significant inhibitory effects on C. albicans (MIC: 0.97 μg/mL), comparable to fluconazole. The presence of C3‐(3‐chloro‐indolyl) scaffold, combined with diverse electronic effects at N1/C4‐centers, particularly the inclusion of thiophen‐2‐yl motif, greatly influenced the activity of target compounds. Assessment of 4d, 4i‐k and 6d on THLE‐2 cell lines revealed their preferential safety. Molecular docking studies revealed seven compounds with active dual targeting of DNA GyrB and PBP2a proteins, demonstrating a potent broad‐spectrum antibacterial effect. In silico ADME analysis affirms positive drug‐likeness and favorable pharmacokinetic characteristics of indole‐derived hybrids, indicating a promising potential for addressing challenges in evolving multidrug resistance.

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Stereoselective synthesis and in-silico evaluation of C4-benzimidazolyloxyphenyl substituted trans-β-lactam derivatives as promising novel PPARγ activators

Cited by 7 publications

References 25 publications

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

C7‐Halomethylene/methyl‐C3‐thiophenyl‐spirocyclic‐β‐lactams: Synthesis, X‐ray Analysis, Antimicrobial Evaluation, Cytotoxicity Profile and Molecular Docking Interactions

Design, Synthesis and Biological Evaluation of C3‐Indolyl/(3‐chloro‐indolyl)‐C4‐aryl/heteroaryl‐azetidin‐2‐ones

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