1Associate Professor, Department of Pharmaceutics, Raghavendra Institute of Pharmaceutical Education and Research (RIPER) - Autonomous, K R Palli Cross, Chiyyedu, Anantapur, Andhra Pradesh, India
2Assistant Professor, Department of Allied Health Science, Saraswati College of Pharmacy, SGC Group, Gharuan, Mohali, Punjab
3Assistant Professor, Department of Pharmaceutical Chemistry, School of Pharmaceutical sciences, RIMT University, Fatehgarh Sahib, Punjab, India
4Technical Trainer, Chandigarh University, Chandigarh, Punjab, India
5Assistant Professor, Institute of Pharmacy, Assam Don Bosco University, Tapesia, Assam, India
6Lecturer, Department of oral and maxillofacial pathology, Kalinga Institute of Dental Sciences, Khordha District, Odisha, India
7Assistant Professor, Department of Pharmaceutics, Gondia College of Pharmacy, Gondia, Maharashtra, India
8Associate Professor, Department of Biotechnology and Life Science, Mangalayatan University, Aligarh, India
9Associate Professor, Department of Pharmacy Practice, Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, India. Email: dikkatwarmanoj@gmail.com
*Corresponding Author: Manoj S Dikkatwar, Associate Professor, Department of Pharmacy Practice, Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, India. Email: dikkatwarmanoj@gmail.com
Background: Tumor hypoxia is a critical feature of the cancer microenvironment that promotes tumor progression, metastasis, and resistance to therapy. Carbonic anhydrase IX (CA IX) plays a key role in maintaining extracellular acidity and cellular adaptation under hypoxic conditions. Targeting CA IX has therefore emerged as a promising strategy for anticancer drug development (Supuran, 2018).
Objective: The present study aimed to design, synthesize, and biologically evaluate novel 1,3,4-oxadiazole–sulfonamide hybrid derivatives as potential inhibitors of CA IX and to investigate their effects on HIF-1α expression and extracellular pH modulation in hypoxic cancer cells.
Methods: A series of 1,3,4-oxadiazole–sulfonamide hybrids were synthesized through a multistep synthetic approach and structurally characterized using FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry. The synthesized compounds were evaluated for in vitro CA IX inhibitory activity, and IC₅₀ values were determined. Biological studies were conducted using human cancer cell lines cultured under normoxic and hypoxic conditions. The effect of selected compounds on HIF-1α expression was analyzed using Western blot analysis, while extracellular pH changes were monitored to assess modulation of the tumor microenvironment.
Results: The synthesized compounds were successfully obtained and confirmed by spectral analysis. Several derivatives demonstrated significant CA IX inhibitory activity, indicating the pharmacological relevance of combining the sulfonamide pharmacophore with the 1,3,4-oxadiazole scaffold. Cellular studies revealed that selected compounds significantly reduced HIF-1α expression under hypoxic conditions and produced a measurable increase in extracellular pH, suggesting effective targeting of tumor acidity and hypoxia-associated pathways.
Conclusion: The results suggest that 1,3,4-oxadiazole–sulfonamide hybrids are promising CA IX inhibitors capable of modulating tumor hypoxia signaling and extracellular acidification. These compounds may serve as potential lead molecules for the development of novel anticancer agents, warranting further investigation through in vivo studies and molecular optimization.
Keywords: Carbonic anhydrase IX; Tumor hypoxia; 1,3,4-Oxadiazole; Sulfonamide hybrids; HIF-1α; Extracellular pH; Anticancer agents; Enzyme inhibition.
How to cite this article: Mahammed N, Neha, Bhalla P, Singh G, Sharma A, Mahapatra N, Rehapade VT, Singh S, Dikkatwar MS. Targeting Tumor Hypoxia via Carbonic Anhydrase IX: Design, Spectral Characterization, and Integrated Pharmacological Evaluation of 1,3,4-Oxadiazole–Sulfonamide Hybrids with HIF-1α Expression and Extracellular pH Modulation Studies. Int J Drug Deliv Technol. 2026;16(10s): 969-974. DOI: 10.25258/ijddt.16.10s.112
Source of support: Nil.
Conflict of interest: None