Excavations in drug chirality: 1. Cyclothiazide.

Area of Science:

• Medicinal Chemistry
• Pharmaceutical Sciences
• Organic Chemistry

Background:

• Chirality's importance in drug development is recognized, but stereochemical details of older drugs are often overlooked.
• Many chiral drugs were introduced without comprehensive stereochemical identity or composition data.
• Cyclothiazide, an antihypertensive diuretic, is one such older chiral drug with limited available stereochemical information.

Purpose of the Study:

• To investigate the stereochemical composition of the antihypertensive diuretic agent cyclothiazide.
• To determine if pharmaceutical cyclothiazide exists as a single stereoisomer or a mixture.
• To highlight the significance of stereochemical analysis for older drug compounds.

Main Methods:

• Chemical structure analysis of cyclothiazide to predict potential stereoisomers.
• Synthesis of cyclothiazide.
• Analytical techniques including fast-atom-bombardment mass spectrometry, gas-liquid chromatography, chiral and non-chiral high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy.

Main Results:

• Cyclothiazide can exist as eight stereoisomers, potentially forming four racemates.
• Pharmaceutical cyclothiazide was confirmed to be a mixture of all eight stereoisomers as four racemates.
• The endo configuration racemates of cyclothiazide predominated over the exo forms.
• Variations in isomer distribution were observed between different batches of the drug.

Conclusions:

• Pharmaceutical cyclothiazide is a complex mixture of stereoisomers, not a single entity.
• The stereochemical composition of older drugs like cyclothiazide warrants careful investigation.
• Understanding the stereochemistry of existing drugs is essential for comprehensive pharmaceutical research and development.