2. Academic Validation
  3. Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations

Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations

  • Bioorg Chem. 2024 Dec:153:107843. doi: 10.1016/j.bioorg.2024.107843.
Moataz A Shaldam 1,  Mai H A Mousa 2,  Haytham O Tawfik 3,  Ahmed M El-Dessouki 4,  Marwa Sharaky 5,  Mohamed M Saleh 6,  Abdullah Yahya Abdullah Alzahrani 7,  Sana Ben Moussa 8,  Ahmed A Al-Karmalawy 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt. Electronic address: dr_moutaz_986@pharm.kfs.edu.eg.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt. Electronic address: mhatem@ecu.edu.eg.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: haytham.omar.mahmoud@pharm.tanta.edu.eg.
  • 4 Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt. Electronic address: ahmed.desoky@acu.edu.eg.
  • 5 Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt. Electronic address: marwa.sharaky@nci.cu.edu.eg.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: mohamed.magdy@pharm.tanta.edu.eg.
  • 7 Department of Chemistry, Faculty of Science and Arts, King Khalid University, Mohail Assir 61421, Saudi Arabia. Electronic address: ayalzahrani@kku.edu.sa.
  • 8 Department of Chemistry, Faculty of Science and Arts, King Khalid University, Mohail Assir 61421, Saudi Arabia.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Mashreq, Baghdad 10023, Iraq; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt. Electronic address: akarmalawy@horus.edu.eg.
PMID: 39332072 DOI: 10.1016/j.bioorg.2024.107843
Abstract

In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against Telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved Telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful "multitarget-directed drug" for Cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (Telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its Anticancer effects.

Keywords

JAK1/STAT3/TLR4; Multitarget-directed design; Preclinical; Telomerase.

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