Medicinal Chemistry Strategies for the Modification of Bioactive Natural Products

Narcisa Raquel^*
*Correspondence: Narcisa Raquel, Department of Medicinal Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland, Email:

Keywords

Prodrug design • Bioactive natural products • Clinical utility • Medicinal chemistry

Introduction

Bioactive natural products, derived from plants, animals, fungi and microorganisms, have historically served as essential sources of pharmacologically active compounds. Many clinically important drugs, including antibiotics, anticancer agents and cardiovascular drugs, are either natural products or derivatives thereof. Despite their therapeutic potential, natural products often exhibit limitations such as poor aqueous solubility, low bioavailability and susceptibility to metabolic degradation, which can impede their clinical translation. Medicinal chemistry approaches offer promising solutions to address these challenges by modifying the structures of bioactive natural products to enhance their pharmacokinetic and pharmacodynamic properties [1].

Literature Review

Structural optimization involves modifying the chemical structure of natural products to improve their drug-like properties while retaining or enhancing their biological activity. This approach typically includes structural simplification, functional group modifications and stereochemical adjustments. For instance, the structural complexity of natural products can be reduced through deconstruction or fragmentation followed by rational design to generate simplified analogs with improved synthetic accessibility and pharmacological profiles. Additionally, the introduction of polar functional groups, such as hydroxyl or amino groups, can enhance water solubility and facilitate interactions with biological targets, thereby improving potency and selectivity. Stereochemical modifications, including inversion or manipulation of chiral centers, can also influence the biological activity and metabolic stability of natural product derivatives [2,3].

Semi-synthesis involves the chemical modification of natural product scaffolds using synthetic methods to generate analogs with improved pharmacological properties. This approach combines the structural diversity of natural products with the synthetic versatility of medicinal chemistry. Semi-synthetic modifications often target specific functional groups or regions of the natural product molecule to optimize its pharmacokinetic and pharmacodynamic properties. For example, semi-synthesis can enable the introduction of novel substituents or modifications at reactive sites to enhance potency, selectivity, or metabolic stability. Moreover, semi-synthetic analogs can be designed to overcome resistance mechanisms or circumvent toxicity associated with natural products, thereby expanding their therapeutic utility [4].

Prodrug design involves the chemical modification of natural products to improve their pharmaceutical properties, such as solubility, stability and target specificity, through the attachment of pro-moieties. Prodrugs are inactive or less active derivatives of the parent compound that undergo enzymatic or chemical activation in vivo to release the active drug. This strategy can enhance the bioavailability and tissue distribution of natural products by facilitating their absorption, distribution, metabolism and excretion (ADME) characteristics. Common prodrug strategies include esterification, amidation and phosphate masking, which can modulate the physicochemical properties and pharmacokinetic profiles of natural product derivatives. Prodrug design offers a versatile approach to optimize the therapeutic index and overcome formulation challenges associated with natural products.

Molecular hybridization involves the combination of pharmacophores from different natural products or synthetic compounds to generate novel chemical entities with enhanced biological activity and pharmacological properties. This approach exploits the synergistic interactions between structurally distinct molecules to create multifunctional agents with improved efficacy, selectivity and safety profiles. Molecular hybridization can be achieved through rational design or combinatorial methods, such as scaffold hopping, fragment assembly and bioisosteric replacement. By merging the structural features of bioactive natural products with synthetic scaffolds or pharmacophores, molecular hybrids can exhibit improved drug-likeness, target affinity and metabolic stability, thereby accelerating the discovery of novel therapeutics [5,6].

Discussion

Several successful examples demonstrate the efficacy of medicinal chemistry strategies in modifying bioactive natural products for therapeutic applications. For instance, the semi-synthetic modification of the antibiotic erythromycin led to the development of clarithromycin, a second-generation macrolide with improved pharmacokinetic properties and enhanced antibacterial activity against resistant pathogens. Similarly, the structural optimization of the anticancer natural product paclitaxel resulted in the synthesis of docetaxel, a semi-synthetic derivative with superior water solubility and antitumor efficacy. Moreover, the molecular hybridization of artemisinin, a natural product used for malaria treatment, with synthetic peroxide scaffolds led to the discovery of novel antimalarial agents with improved potency and resistance profiles.

Conclusion

Medicinal chemistry strategies play a pivotal role in modifying bioactive natural products to enhance their pharmacological properties and therapeutic potential. Structural optimization, semi-synthesis, prodrug design and molecular hybridization offer versatile approaches to overcome the limitations associated with natural products, thereby facilitating the discovery and development of novel therapeutics. By integrating knowledge of medicinal chemistry, organic synthesis and pharmacology, researchers can continue to harness the vast chemical diversity of natural products for the treatment of various diseases.

Acknowledgement

None.

Conflict of Interest

None.

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