Design, synthesis and biological evaluation of 2,3-dihydroimidazo[2,1-b]thiazoles as dual EGFR and IGF1R inhibitors

Gadekar, Pradip K.; Urunkar, Ganesh; Roychowdhury, Abhijit; Sharma, Rajiv; Bose, Julie; Khanna, Smriti; Damre, Anagha; Sarveswari, S.

doi:10.1016/j.bioorg.2021.105151

Cited by 16 publications

(4 citation statements)

References 14 publications

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“…Compound 70 has displayed promising activity with an IC 50 value of 52 nM against IGF1R and an IC 50 value of 35.5 nM against EGFR with an acceptable PK profile [ 73 ]. Compounds 71 and 72 both exhibited activity against HIV-1 in LEDGF/p75 contact, while 71 displayed a MIC value of 15.6 μg/mL against S. aureus , and 72 displayed a comparable MIC value against B. cereus [ 74 ] (see Figure 15 ).…”

Section: Five-membered Heterocyclic Compoundsmentioning

confidence: 99%

“…Figure 15. Chemical structures of imidazole hybrids with significant biological activities.Compound 70 has displayed promising activity with an IC 50 value of 52 nM against IGF1R and an IC 50 value of 35.5 nM against EGFR with an acceptable PK profile[73]. Compounds 71 and 72 both exhibited activity against HIV-1 in LEDGF/p75 contact, while 71 displayed a MIC value of 15.6 µg/mL against S. aureus, and 72 displayed a comparable MIC value against B. cereus[74] (see Figure15).A new library of 2-(5-aryl-1H-imidazol-1-yl) compounds 73, 74, 75 were designed, synthesized, and evaluated for their inhibitory activity against the HIV-1 Vpu and BST-2 protein interaction[75].…”

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confidence: 99%

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An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Ebenezer

Jordaan

Carena

et al. 2022

IJMS

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Heterocyclic compounds are a class of compounds of natural origin with favorable properties and hence have major pharmaceutical significance. They have an exceptional adroitness favoring their use as diverse smart biomimetics, in addition to possessing an active pharmacophore in a complex structure. This has made them an indispensable motif in the drug discovery field. Heterocyclic compounds are usually classified according to the ring size, type, and the number of heteroatoms present in the ring. Among different heterocyclic ring systems, nitrogen heterocyclic compounds are more abundant in nature. They also have considerable pharmacological significance. This review highlights recent pioneering studies in the biological assessment of nitrogen-containing compounds, namely: triazoles, tetrazoles, imidazole/benzimidazoles, pyrimidines, and quinolines. It explores publications between April 2020 and February 2022 and will benefit researchers in medicinal chemistry and pharmacology. The present work is organized based on the size of the heterocyclic ring.

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Section: Five-membered Heterocyclic Compoundsmentioning

confidence: 99%

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confidence: 99%

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Ebenezer

Jordaan

Carena

et al. 2022

IJMS

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“…One of the most potent IGF-1R inhibitors, phenylpyrazolo[3,4- d ]pyrimidine, showed fabulous antitumor activities in the NSCLC induced xenograft and allograft model [ 97 ]. Gadekar and colleagues proposed 2,3-dihydroimidazo[2,1- b ]thiazoles as dual EGFR and IGF1R inhibitors with reasonable drug likeness properties [ 98 ]. Tyrphostin AG 1024, a selective inhibitor of IGF-1R, markedly increases the response of tumor cells to ionizing radiation [ 99 ].…”

Section: Recent Updates On Selective Tyrosine Kinase Inhibitors In Pre-clinical Studiesmentioning

confidence: 99%

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Mongre

Mishra

Shukla

et al. 2021

IJMS

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GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types.

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“…To counter such problems in metabolism, biotransformation studies are becoming significant in guiding the modification of a lead series during drug discovery and in characterizing lead candidates . One of the commonly used strategies in medicinal chemistry is the use of bioisosteres to improve the drug-like properties and resolve such issuses . Bioisosterism is used in the modification of lead compounds that eliminate toxicity and enhance the potency and pharmacokinetic properties of the molecule.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and the Effects of (E)-9-Oxooctadec-10-en-12-ynoic Acid Analogues to Promote Glucose Uptake

Kshirsagar

Gadekar

Khedkar³

et al. 2021

ACS Omega

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(E)-9-Oxooctadec-10-en-12-ynoic acid is found to mediate its antidiabetic activity by increasing insulin-stimulated glucose uptake in L6 myotubes by activating the phosphoinositide 3-kinase (PI3K) pathway. A simultaneous study of site-specific modification followed by structure–activity relationship provides a tremendous scope for exploiting the bioactivity of the parent molecule. Therefore, in the present study, we focused on site-specific modification of (E)-9-oxooctadec-10-en-12-ynoic acid (1) to generate multiple derivatives and extensive structure–activity relationship (SAR) studies. We have done structural base design and synthesized a series of amides from acid compound 1. Compound 1 consists of an acid functionality, which is known for its metabolism-related liabilities. The SAR has been generated using scaffolds of different antidiabetic drugs such as biguanides, sulfonylureas, thiazolidinediones/glitazones, peroxisome proliferator-activated receptors, K + ATP, α-glucosidase inhibitors, and others. Furthermore, the study demonstrates and explains the promising derivatives and importance of SAR of the compound (E)-9-oxooctadec-10-en-12-ynoic acid. In order to gain mechanistic insights, a molecular docking study was performed against PI3K, which could identify the binding modes and thermodynamic interactions governing the binding affinity. According to our research, compounds 5, 6, 27, 28, 31, 32, and 33 are the best compounds from the series having EC50 values of 15.47, 8.89, 7.00, 13.99, 8.70, 12.27, and 16.14 μM, respectively.

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Design, synthesis and biological evaluation of 2,3-dihydroimidazo[2,1-b]thiazoles as dual EGFR and IGF1R inhibitors

Cited by 16 publications

References 14 publications

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Design, Synthesis, and the Effects of (E)-9-Oxooctadec-10-en-12-ynoic Acid Analogues to Promote Glucose Uptake

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