New 1,2,3-triazole/1,2,4-triazole hybrids linked to oxime moiety as nitric oxide donor selective COX-2, aromatase, B-RAF^V600E and EGFR inhibitors celecoxib analogs: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis and molecular modeling study

Abstract

A new series of bis-triazole 19a-l was synthesised for the purpose of being hybrid molecules with both anti-inflammatory and anti-cancer activities and assessed for cell cycle arrest, NO release. Compounds 19c, 19f, 19h, 19 l exhibited COX-2 selectivity indexes in the range of 18.48 to 49.38 compared to celecoxib S.I. = 21.10), inhibit MCF-7 with IC₅₀ = 9–16 μM compared to tamoxifen (IC₅₀ = 27.9 μM). and showed good inhibitory activity against HEP-3B with IC₅₀ = 4.5–14 μM compared to sorafenib (IC₅₀ = 3.5 μM) (HEP-3B). Moreover, derivatives 19e, 19j, 19k, 19 l inhibit HCT-116 with IC₅₀ = 5.3–13.7 μM compared to 5-FU with IC₅₀ = 4.8 μM (HCT-116). Compounds 19c, 19f, 19h, 19 l showed excellent inhibitory activity against A549 with IC₅₀ = 3–4.5 μM compared to 5-FU with IC₅₀ = 6 μM (A549). Compounds 19c, 19f, 19h, 19 l inhibit aromatase (IC₅₀ of 22.40, 23.20, 22.70, 30.30 μM), EGFR (IC₅₀ of 0.112, 0.205, 0.169 and 0.066 μM) and B-RAF^V600E (IC₅₀ of 0.09, 0.06, 0.07 and 0.05 μM).

Keywords:

• Aromatase inhibition
• bis-Triazole
• B-RAF^V600E
• inhibition
• cyclooxygenase-2 inhibition
• (EGFR) inhibition
• nitric oxide donor

Acknowledgement

The authors thank Dr. Nada S. Abd El-Wahab, Pharmaceutical analytical Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Egypt for carrying out nitric oxide release experiment.

Authors’ contributions

Idea was created by Wael A. A. Fadaly. Synthesis of the compounds was carried out by Wael A. A. Fadaly and Mohamed T. M. Nemr. Discussion part was reedited by Fatma E. A. Mohamed and Marwa M. Abdelhakeem. Introduction part was reedited by Khaled R. A. Abdellatif. Docking studies were carried out by Taha H. Zidan. In vitro screening and IC₅₀ determinations were performed by Nour N. Abu Jayab and Hany A. Omar. All the authors shared in writing, reviewing the manuscript in its final form.

Disclosure statement

The authors have declared no conflict of interest.

Additional information

Funding

The authors declare that they have no financial sources of support for this study.