Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening

Area of Science:

• Pharmaceutical Science
• Materials Science
• Crystallography

Background:

• Dihydrofolate reductase (DHFR) inhibitors, such as trimethoprim (TMP) and pyrimethamine (PMA), are crucial active pharmaceutical ingredients (APIs).
• 2,4-diaminopyrimidine (DAP) represents the core pharmacophore for these DHFR inhibitors.
• Co-crystallization is a key strategy for modifying API properties and improving drug delivery.

Purpose of the Study:

• To investigate the potential of using the DAP pharmacophore as a predictive guide for co-crystal screening of DHFR inhibitors.
• To explore co-crystal formation between DAP, TMP, PMA, and various co-formers, including pyridinecarboxamides and xanthines (theophylline and caffeine).
• To evaluate the efficacy of in silico screening combined with experimental methods for identifying novel co-crystals.

Main Methods:

• In silico co-crystal screening utilizing BIOVIA COSMOquick.
• Experimental screening employing mechanochemistry.
• Characterization techniques including binary phase diagrams, FTIR, and XRPD.
• Single-crystal X-ray diffraction for structure determination.

Main Results:

• In silico predictions of poor co-crystallization with pyridinecarboxamides were experimentally confirmed, with only DAP + nicotinamide yielding a successful outcome.
• Successful synthesis of multicomponent solid forms was achieved for all three target molecules (DAP, TMP, PMA) with theophylline (THEO).
• DAP co-crystals with theophylline exhibited a notable variety of stoichiometries, and crystalline structures of a (1:2) TMP:THEO co-crystal and a (1:2:1) DAP:THEO:ethyl acetate solvate were determined.

Conclusions:

• The pharmacophore of DHFR inhibitors can serve as a valuable guide in co-crystal screening processes.
• Similar trends in solid-state association and molecular aggregation were observed, guided by common supramolecular synthons.
• This approach facilitates the discovery of novel crystalline forms with potentially improved pharmaceutical properties.