Design and synthesis of hybrid compounds as novel drugs and medicines

Abstract

The development of highly effective conjugate chemistry approaches is a way to improve the quality of drugs and of medicines. The aim of this paper is to highlight and review such hybrid compounds and the strategies underpinning their design. A variety of unique hybrid compounds provide an excellent toolkit for novel biological activity, e.g. anticancer and non-viral gene therapy (NVGT), and as templates for killing bacteria and preventing antibiotic drug resistance. First we discuss the anticancer potential of hybrid compounds, containing daunorubicin, benzyl- or tetrahydroisoquinoline-coumarin, and cytotoxic NSAID-pyrrolizidine/indolizine hybrids, then NVGT cationic lipid-based delivery agents, where steroids or long chain fatty acids as the lipid moiety are bound to polyamines as the cationic moiety. These polyamines can be linear as in spermidine or spermine, or on a polycyclic sugar template, aminoglycosides kanamycin and neomycin B, the latter substituted with six amino groups. They are highly efficient for the delivery of both fluorescent DNA and siRNA. Molecular precedents can be found for the design of hybrid compounds in the natural world, e.g., squalamine, the first representative of a previously unknown class of natural antibiotics of animal origin. These polyamine-bile acid (e.g. cholic acid type) conjugates display many exciting biological activities with the bile acids acting as a lipidic region and spermidine as the polycationic region. Analogues of squalamine can act as vectors in NVGT. Their natural role is as antibiotics. Novel antibacterial materials are urgently needed as recalcitrant bacterial infection is a worldwide problem for human health. Ribosome inhibitors founded upon dimers of tobramycin or neomycin, bound as ethers by a 1,6-hexyl linker or a more complex diether-disulfide linker, improved upon the antibiotic activity of aminoglycoside monomers by 20- to 1200-fold. Other hybrids, linked by click chemistry, conjugated ciprofloxacin to neomycin, trimethoprim, or tedizolid, which is now in clinical trials.

Fig. 1. A linker that can be degraded enzymatically (by bacterium-specific enzymes with regard to a hybrid antibacterial drug) results in two useful drugs in a hybrid pro-drug approach. A linker that cannot be degraded enzymatically and holds two the same or different pharmacophores bound together represents the hybrid drug strategy.

Fig. 2. Dimeric ligands possess potential advantages over monomers. The hypothetical model for monomeric ligand binding shown in 1′, 2′, and 3′ show that monomeric ligands, L1 and L2 (which may possess different biological activity, e.g., aminoglycoside antibiotics, DNA intercalators, polyamines), may dissociate rapidly after binding to their binding sites (a1 and a2) in an independent manner. The hypothetical model for dimeric ligands, shown in panels 1–6, will allow for changed kinetics. Thus in 1–3, L2 may be brought into close proximity to a2 by the binding of L1 to a1, and may be held close to the site even after dissociation, and thus will have an increased chance of binding again. In addition, should both moieties dissociate there is an increased chance that one of the moieties will interact with the other binding site, as shown in panels 4–6. This is therefore an advantage of incorporating the linker (shown in green) that might then allow the additional association of L2 to a1.

Fig. 3. Daunorubicin dimer linked by a p-xylene (WP631) (left), monomeric daunorubicin bound to DNA, the NH₂ groups are within 6 Å of one another (middle), daunorubicin dimer linked by a triazole via click-chemistry (right).

Fig. 4. Daunorubicin secondary amine conjugates (centre) prepared from the aldehyde piperonal (left) and its dimethoxy derivative (centre) and daunorubicin amide from piperonylic acid (right).

Fig. 5. Coumarin-benzimidazole hybrids.

Fig. 6. THIQ-coumarin hybrid.

Fig. 7. Ibuprofen or ketoprofen-pyrrolizine hybrids.

Fig. 8. The three parts of a cationic lipid: the hydrophilic moiety (L1), e.g., a polyamine, the linker (shown here as a green line), e.g., a carbamate or amide functional group, and a lipophilic moiety (L2).

Fig. 9. Coupling spermine with long chain fatty acids.

Fig. 10. Di-fatty acid amides of spermine.

Fig. 11. Coupling kanamycin (upper) or neomycin (lower) to a cholesteryl moiety.

Fig. 12. Squalamine, a naturally occurring spermidine bile acid conjugate found in sharks.

Fig. 13. Aminoglycoside antibiotics.

Fig. 14. Dimeric neomycin bound by a disulfide containing chain linker.

Fig. 15. Dimeric tobramycin bound by a 1,6-hexyl diether linker.

Fig. 16. A homo-dimeric tobramycin linked triazole synthesized via click-chemistry.

Fig. 17. Neomycin B-ciprofloxacin hybrids, with aromatic and aliphatic bound triazole linkers.

Fig. 18. Trimethoprim-ciprofloxacin hybrid.

Fig. 19. Cadazolid was synthesised by linking tedizolid and ciprofloxacin.

Fig. 20. Dithiourea-diamine (A and B) and lipidic polyamine (C and D) hybrid molecules with antibacterial and antibiofilm activity.

Abdulaziz H. Alkhzem

Timothy J. Woodman

Ian S. Blagbrough