New quinoxaline compounds as DPP-4 inhibitors and hypoglycemics: design, synthesis, computational and bio-distribution studies

Syam, Yasmin M.; Anwar, Manal M.; El-Karim, Somaia S. Abd; Elseginy, Samia A.; Essa, Basma M.; Sakr, Tamer M.

doi:10.1039/d1ra06799k

Cited by 17 publications

(11 citation statements)

References 79 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…43 A biodistribution study was rendered for one of the hopeful antimicrobial candidates 6b as a representative example to explore its in vivo pharmacokinetic behavior and body organ uptakes, besides its elimination pathway via radiolabeling with 131 I. 44,45 2.3.1. Radiolabeling of the Compound 6b.…”

Section: Dhfr Inhibitory Efficiencymentioning

confidence: 99%

New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies

Dawood,

Sayed,

Tohamy

et al. 2023

ACS Omega

View full text Add to dashboard Cite

The antibiotic resistance problems constitute a considerable threat to human health worldwide; thus, the discovery of new antimicrobial candidates to conquer this issue is an imperative requirement. From this view, new thiophenyl-pyrazolyl-thiazole hybrids 3–10 were synthesized and screened for their antibacterial efficiency versus Gram – and Gram + bacterial strains compared to the reference drug amoxicillin. It was noticed that the new hybrids displayed significant antibacterial efficacy versus Gram – bacteria, especially against Pseudomonas aeruginosa. Also, all the screened candidates demonstrated a noticeable antifungal effect against Candida albicans (MICs = 3.9–125 μg/mL) relative to fluconazole (MIC = 250 μg/mL). Moreover, the new hybrids were investigated for their antituberculosis potency against Mycobacterium tuberculosis (RCMB 010126). Derivatives 4c, 6b, 8b, 9b, and 10b demonstrated prominent antituberculosis efficiency (MICs = 0.12–1.95 μg/mL) compared with the reference drug isoniazid (MIC = 0.12 μg/mL). The latter derivatives were further assessed for their inhibitory potency versus M. tuberculosis DHFR enzyme. The compounds 4c, 6b and 10b presented a remarkable suppression effect with IC50 values of 4.21, 5.70, and 10.59 μM, respectively, compared to that of trimethoprim (IC50 = 6.23 μM). Furthermore, biodistribution profile using radiolabeling way revealed a perceived uptake of 131I-compound 6b into infection induced models. The docking study for the new hybrids 4c, 6b, 8b, 9b and 10b was performed to illustrate the various binding modes with Mtb DHFR enzyme. In silico ADMET studies for the most potent inhibitors 4c, 6b and 10b were also accomplished to predict their pharmacokinetic and physicochemical features.

show abstract

Section: Dhfr Inhibitory Efficiencymentioning

confidence: 99%

New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies

Dawood,

Sayed,

Tohamy

et al. 2023

ACS Omega

View full text Add to dashboard Cite

show abstract

“…Molecular docking studies were performed with the most promising candidates 45 a, 46 a, 47 a, and 47 b where all the compounds displayed good binding with the active pockets of DPP-4 (PDB ID: 3WQH). [42] Triloknadh et al, described the design, synthesis, in silico docking studies and biological evaluation of novel quinoxalinehydrazide hydrazone-1,2,3-triazole hybrids as α-glucosidase inhibitors (48 and 49, Figure 13). All the synthesized compounds 48 and 49 were screened for in vitro α-glucosidase inhibitory activity and the results showed that analogs 48 a-48 c and 49 a were the most potent candidates of the series with IC 50 values of 21.92, 22.32, 23.58, and 24.50 μg/mL, respectively when compared with reference drug acarbose (22.32 μg/mL).…”

Section: Antidiabetic Activitymentioning

confidence: 99%

“…Further, synthesized compounds were evaluated for in vivo anti‐hyprglycemic effect by intraperitoneal glucose tolerance test (IPGTT) where results unveiled that compounds 46 a , 47 b and 47 a were the most potent compounds. Molecular docking studies were performed with the most promising candidates 45 a , 46 a , 47 a , and 47 b where all the compounds displayed good binding with the active pockets of DPP‐4 ( PDB ID: 3WQH ) [42] …”

Section: Pharmacological Activities Of Quinoxaline‐based Compoundsmentioning

confidence: 99%

A Review on Multipurpose Potential of Bioactive Heterocycle Quinoxaline

2023

View full text Add to dashboard Cite

In last few decades, nitrogen‐containing heterocycles have maintained their status as an important core of FDA‐approved drugs and medicinally active compounds. Quinoxaline is one such class of nitrogen‐containing scaffold that has become a subject of extensive research as it possess a plethora of biological activities. Molecular hybridization is a versatile and rational approach to drug design that involves the combination of two bioactive molecules possessing distinct intrinsic activity into a single scaffold for enhancing their therapeutic potential. In view of this, the advancement and potential of quinoxaline hybrids bearing thiazole, triazole, oxadiazole, pyrrolizines, pyrazole, etc. have attracted the keen attention of researchers to explore their therapeutic ability against different biological targets. The present review includes the research in the recent years (2018–2023) and addresses the graceful advancements in the studies related to quinoxaline‐based small molecules including their synthetic routes, biological activities and structure‐activity relationships. We anticipate that this review article will provide comprehensive knowledge of pharmacological importance of quinoxaline analogues and will fulfill the need of scientific community in designing and developing efficacious novel molecules.

show abstract

“…Omarigliptin is also a DPP-4 inhibitor with a sulfonamide portion, as depicted in Figure 1 . Omarigliptin is distinct from other antidiabetic drugs since it has a long half-life, may be taken orally, and only needs to be dosed once every seven days [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay

Vawhal¹,

Jadhav²,

Kaushik

et al. 2023

Molecules

View full text Add to dashboard Cite

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

show abstract

New quinoxaline compounds as DPP-4 inhibitors and hypoglycemics: design, synthesis, computational and bio-distribution studies

Abstract: The current work represents the design and synthetic approaches of a new set of compounds 6–10 bearing the 1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide scaffold.

Cited by 17 publications

References 79 publications

New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies

New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies

A Review on Multipurpose Potential of Bioactive Heterocycle Quinoxaline

Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay

Contact Info

Product

Resources

About