Conjugation as a Tool in Therapeutics: Role of Amino Acids/Peptides-Bioactive (Including Heterocycles) Hybrid Molecules in Treating Infectious Diseases

Abstract

Peptide-based drugs are gaining significant momentum in the modern drug discovery, which is witnessed by the approval of new drugs by the FDA in recent years. On the other hand, small molecules-based drugs are an integral part of drug development since the past several decades. Peptide-containing drugs are placed between small molecules and the biologics. Both the peptides as well as the small molecules (mainly heterocycles) pose several drawbacks as therapeutics despite their success in curing many diseases. This gap may be bridged by utilising the so called 'conjugation chemistry', in which both the partners are linked to one another through a stable chemical bond, and the resulting conjugates are found to possess attracting benefits, thus eliminating the stigma associated with the individual partners. Over the past decades, the field of molecular hybridisation has emerged to afford us new and efficient molecular architectures that have shown high promise in medicinal chemistry. Taking advantage of this and also considering our experience in this field, we present herein a review concerning the molecules obtained by the conjugation of peptides (amino acids) to small molecules (heterocycles as well as bioactive compounds). More than 125 examples of the conjugates citing nearly 100 references published during the period 2000 to 2022 having therapeutic applications in curing infectious diseases have been covered.

Keywords: amino acids; bioactive molecules; conjugation chemistry; heterocycles; peptides.

Figure 1

Various techniques used in drug discovery.

Figure 2

Increasing trend in peptide-based drugs.

Figure 3

Total number of peptide-based drugs in different stages of drug discovery and development.

Figure 4

The US FDA approved drugs since 2014.

Figure 5

2022-based global pharmaceutical market.

Figure 6

Different categories of peptide-based drugs.

Figure 7

Different strategies used in peptidomimetics.

Figure 8

Pros and cons of amino acids/peptides and heterocycles in therapeutic development and the effect of their conjugation.

Figure 9

Some of the drugs in the market resulting from hybridisation of small molecules to peptides.

Figure 10

Different therapeutic applications of the conjugates.

Figure 11

Colour coding used in this article.

Figure 12

Peptides-benzodiazepine (BDZ-2) hybrid molecules.

Figure 13

Amino acids/peptides-temozolomide and mitozolomide hybrid molecules.

Figure 14

Tetrazole-based peptidomimetics.

Figure 15

8-quinolinamine-amino acid conjugates.

Figure 16

Amino acids-oxoazabenzo[de]anthracenes hybrid molecules.

Figure 17

Amino acids conjugated to benzylpiperazine derivatives.

Figure 18

Benzimidazolo-peptide conjugates.

Figure 19

Imidazolo-/quinazolino-peptide derivatives.

Figure 20

Glycosidic analogues of His dipeptides.

Figure 21

4,6-disubstituted quinazoline-α-amino acid hybrid molecules.

Figure 22

Oligoarginine-daunomycin conjugates.

Figure 23

Amino acids-diphenylmethylpiperazine hybrid molecules.

Figure 24

L-amino acids conjugated to 10-methoxy-dibenz[b,f]azepine.

Figure 25

Indoloquinolizidine-peptide hybrids.

Figure 26

Isoluminol conjugated to amino acid derivatives.

Figure 27

Amino acid conjugated to Ara-C (cytarabine) analogues.

Figure 28

Quinazolinone conjugated to elastin-based peptide fragments.

Figure 29

Amino acid conjugated to 5H-dibenz[b,f]azepine.

Figure 30

Peptides conjugated with 4-(4-oxo-3,4-dihydroquinazolin-2-yl) butanoic acid.

Figure 31

Amino acids conjugated to piperoyl derivatives.

Figure 32

1,2,4-triazolo-naphthalene and thiadiazole analogues conjugated amino acid derivatives.

Figure 33

Lys-quinazolinone conjugates.

Figure 34

Amino acids conjugated to benzisoxazole derivatives.

Figure 35

Amino acids conjugated to nifedipine.

Figure 36

β-carboline alkaloid-peptide conjugates.

Figure 37

Amino acids/peptides conjugated bis-8-aminoquinolines.

Figure 38

Benzyl esters of N-isoquinoline-3-carbonyl-L-leucine and N-isoquinoline-3-carbonyl-L-threonine.

Figure 39

Amino acids-conjugated thiazoles.

Figure 40

Amino acid/peptides conjugated to heterocycles.

Figure 41

Elastin-based peptides conjugated to 1-(2,3-dichlorophenyl) piperazine.

Figure 42

Sansalvamide A peptidomimetics.

Figure 43

4-aminoquinoline/cinnamic acid conjugates.

Figure 44

8-aminoquinolines conjugated amino acids/dipeptides/pseudopeptides analogues.

Figure 45

Glu conjugated to 3-(1-piperazinyl)-1,2-benzisothiazole.

Figure 46

Quinazolinone conjugated to shorter analogues of Bactenecin 7.

Figure 47

Pro/Gly conjugated with benzisoxazole derivatives.

Figure 48

Amino acid conjugated to quinine.

Figure 49

Peptides conjugated to betulonic acid derivatives.

Figure 50

Imidazole-amino acids conjugates.

Figure 51

Urea/thiourea derivatives of amino acids conjugated 2,3-dichlorophenyl piperazine.

Figure 52

Au^I N and S-heterocyclic carbenes (NSHC)-derived peptides.

Figure 53

Amino acid conjugated to metronidazole/sulphadiazine/quinolone.

Figure 54

Naphthoquinone amide derivatives.

Figure 55

Triazole conjugated cycloheptapeptides.

Figure 56

Amino acids-[3-(4-piperidyl)-6-fluoro-1,2-benzisoxazole] conjugates.

Figure 57

Pentapeptides conjugated to 3-(1-piperazinyl)-1,2-benzisothiazole.

Figure 58

Neocryptolepine-amino acids analogues.

Figure 59

Peptides conjugated to indoloquinolizidine.

Figure 60

Amino acids conjugated to fluoroquinolone-quinolone.

Figure 61

Amino acids–imidazole conjugates.

Figure 62

Amino acid-xanthone derivatives.

Figure 63

Amino acids linked quinazolinones.

Figure 64

Quinoxaline conjugated to peptides.

Figure 65

Coumarin/quinolinone conjugated to N-protected amino acids.

Figure 66

N-α-amino acids conjugated to phthalimide moieties.

Figure 67

Peptides conjugated to 6-fluoro-3-(piperidin-4-yl) benzo[d]isoxazole.

Figure 68

D- and L-Glu derivatives having N-benzylpiperidine.

Figure 69

Amino acids conjugated to 2,3-dichlorophenyl piperazine.

Figure 70

N-substituted α-amino acids analogues consisting hexahydropyrimidine moiety.

Figure 71

Tocopherol-based cationic lipids conjugated to peptides.

Figure 72

4,5-diarylisoxazoles conjugated to amino acids.

Figure 73

Leu linked sulphonamide-quinazolinone hybrid derivatives.

Figure 74

Peptide conjugates of pyrazine derivatives.

Figure 75

4-anilinoquinazoline-amino acid derivatives.

Figure 76

Doxorubicin-curcumin conjugated to cyclic peptide analogues.

Figure 77

Amino acid/Peptides conjugated to benzimidazole derivatives.

Figure 78

Oligoarginine conjugated to vindoline analogues.

Figure 79

Dipeptides/tetrapeptides conjugated to s-triazine analogues.

Figure 80

Glycinocin analogues.

Figure 81

8-quinolinamines conjugated to amino acids.

Figure 82

Amino acids conjugated to piperazine, benzisoxazole and quinazolinone derivatives.

Figure 83

Amino acids (Glu and Asp) linked bis-hydrazones of quinazolinones.

Figure 84

Tryptophan conjugated to imidazolo-derived thioureas/ureas.

Figure 85

Amino acids-quinazolinone-Schiff bases.

Figure 86

Peptides conjugated to quinazolinones.

Figure 87

N¹,N³-bis-(1-oxopropan-2-yl) isophthalamide-based derivatives.

Figure 88

Quinazolinones and 1,4-benzodiazepine-2,5-diones conjugated to amino acids.

Figure 89

Amino acids conjugated to quinazolinone-Schiff bases.

Figure 90

Curcumin bis-conjugates (111) of different N-protected amino acids.

Figure 91

Furan-conjugated tripeptides.

Figure 92

Coumarin-amino acid derivatives.

Figure 93

Levofloxacin (LVX) conjugated cell penetrating peptides.

Figure 94

Piperazine-bridged pseudopeptidic thiourea/urea derivatives.

Figure 95

PPA conjugated to antimicrobial peptide.

Figure 96

Analogues of (KLAKLAK)₂-NH₂ and their derivatives.

Figure 97

Lys-conjugated heterocycles.

Figure 98

Dipeptides conjugated to THPA.

Figure 99

Peptide derivatives conjugated to naphthalene moiety.

Figure 100

α-amino carboxamide derivatives.

Figure 101

α-aminophosphonate analogues.

Figure 102

Aurantiamide acetate derivatives with amino acids/peptides.

Figure 103

Chiral dipeptide thioureas containing α-amino phosphate analogues.

Figure 104

Terminal functionalised dipeptide derivatives.

Figure 105

Phosphonate thioureas containing amino acids.