Design and Synthesis of Novel Antimicrobial Agents

Abstract

The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to antibiotics' availability over the counter in many nations, antibiotic resistance is linked to overuse, abuse, and misuse of these drugs. The World Health Organization (WHO) recognized 12 families of bacteria that present the greatest harm to human health, where options of antibiotic therapy are extremely limited. Therefore, this paper reviews possible new ways for the development of novel classes of antibiotics for which there is no pre-existing resistance in human bacterial pathogens. By utilizing research and technology such as nanotechnology and computational methods (such as in silico and Fragment-based drug design (FBDD)), there has been an improvement in antimicrobial actions and selectivity with target sites. Moreover, there are antibiotic alternatives, such as antimicrobial peptides, essential oils, anti-Quorum sensing agents, darobactins, vitamin B6, bacteriophages, odilorhabdins, 18β-glycyrrhetinic acid, and cannabinoids. Additionally, drug repurposing (such as with ticagrelor, mitomycin C, auranofin, pentamidine, and zidovudine) and synthesis of novel antibacterial agents (including lactones, piperidinol, sugar-based bactericides, isoxazole, carbazole, pyrimidine, and pyrazole derivatives) represent novel approaches to treating infectious diseases. Nonetheless, prodrugs (e.g., siderophores) have recently shown to be an excellent platform to design a new generation of antimicrobial agents with better efficacy against multidrug-resistant bacteria. Ultimately, to combat resistant bacteria and to stop the spread of resistant illnesses, regulations and public education regarding the use of antibiotics in hospitals and the agricultural sector should be combined with research and technological advancements.

Keywords: antibiotic; antimicrobial agents; antimicrobial peptides; nanoparticles; resistance; siderophores.

Figure 1

Chemical structure of penicillins, cephalosporins, carbapenems, monocyclic β-lactams, clavulanic acid (β-lactamase inhibitors), vancomycin, teicoplanin, telavancin, dalbavancin, and oritavancin.

Figure 2

Chemical structure of polymyxins, daptomycin, amphomycin, friulimicin, ramoplanin, and empedopeptin.

Figure 3

Chemical structure of rifampin, rifabutin, rifapentine, streptomycin, apramycin, tobramycin, gentamycin, amikacin, neomycin, arbekacin, and plazomicin.

Figure 4

Chemical structure of nalidixic acid, enoxacin, norfloxacin, ciprofloxacin, ofloxacin, lomefloxacin, sparfloxacin, grepafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, gemifloxacin, trovafloxacin, arenoxacin, sulfamethoxazole, trimethoprim, erythromycin, clarithromycin, azithromycin, fidaxomicin, and telithromycin.

Figure 5

Chemical structure of chlortetracycline, oxytetracycline, tetracycline, demeclocycline, doxycycline, minocycline, lymecycline, meclocycline, methacycline, rolitetracycline, tigecycline, omadacycline, sarecycline, eravacycline, linezolid, sutezolid, eperezolid, delpazolid, tedizolid, tedizolid phosphate, radezolid, and TBI-223.

Figure 6

Chemical structure of quinupristin, pristinamycin, virginiamycin, chloramphenicol, thiamphenicol, florfenicol, lincomycin, and clindamycin.

Figure 7

Mechanism of antimicrobial resistance which include reduce intracellular antibiotic concentration, antibiotic inactivation, and target site alteration.

Figure 8

Strategies for combating antibiotic resistance including, nanotechnology, computational methods, antibiotic alternatives, drug repurposing, synthesis of novel antibacterial agents, prodrugs, awareness, and knowledge of antibiotic prescribing.

Figure 9

Chemical structure of cefoperazone sodium (1), caffeine (2), ricinine (3), anthraquinones (4), emodin (5), chrysophanol (6), elipyrone A (7), delafloxacin (8), thymoquinone (9), N-[3-(aminomethyl)phenyl]-5-chloro-3- methylbenzothiophene-2-sulfonamide (10), piperidinylpyrimidine derivatives (11), thiolactomycin (TLM) (12), pantetheine analog (PK940) (13), BDM31369 (14), BDM31827 (15), 4-Iodo-N-prop-2-ynylbenzenesulfonamide (BDM43266) (16), Tetrahydro-1-benzothiophene (THBTP) Analogue (17), 2-(aminomethyl)benzothiazole (18), NMR446 (19), L-canavanine (20), and N-(5-(azepan-1-ylsulfonyl)-2-methoxyphenyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide (21).

Figure 10

Chemical structure of protonectin (22), Tbt-β^2,2 h bis-Arg-OMe compound (23) camphor (24), 1,8-cineole (25) alpha-pinene (26), trans-chrysanthenyl acetate (27), thymol (28), aromadendrene (29), and β-caryophyllene (30), carvacrol (31), limonene (32), cinnamaldehyde (33), Hamamelitannin (34), (N-(((2R,3R,4S)-4-(benzamidomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-chlorobenzamide) (35), (ethyl 4-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)benzoate (36), ethyl 4-((5-amino-3-((4-(dimethylamino)benzylidene)amino)-1H-pyrazol-4-yl)diazenyl)benzoate (37), ethyl-4-((2-amino-5,7-dimethylpyrazolo [1,5-a]pyrimidin-3-yl)diazenyl)benzoate (38), ethyl-4-((2,7-diamino-6-cyano-5-(4-(dimethylamino)phenyl)pyrazolo [1,5-a]pyrimidin-3-yl)diazenyl)benzoate (39), and ethyl-4-((2-amino-6-cyano-5-(4-(dimethylamino)phenyl)-7-hydroxypyrazolo [1,5-a]pyrimidin-3-yl)diazenyl)benzoate) (40), ML364 (41), silybins AB (42, 43), silychristin A (44), and halogenated flavonolignans derivatives (45).

Figure 11

Chemical structure of NOSO-502 (46), 18β-glycyrrhetinic acid (GRA) (47), Darobactin A (48), MRL-494 (49), trans-Δ-9-tetrahydrocannabinol (THC) (50), cannabidiol (CBD) (51), cannabinol (52), cannabigerol (CBG) (53), and cannabichromene (54).

Figure 12

Chemical structure of ticagrelor (55), M5 AR-C133913 (56), M7 (57), M8 AR-C124910 (58), Mitomycin C (MMC) (59), auranofin (60), pentamidine (62), and zidovudine (AZT) (63).

Scheme 1

Synthesis of series of lactones derivatives from β-cyclocitral (A) and halogenated lactones (B,C). Reagents and condition of (A): (a) NaBH₄,H₂O/CH₃OH, rt., 3 h, 97%; (b) CH₃C(OC₂H₅)₃, CH₃CH₂COOH, 137 °C, 12 h, 71%; (c) KOH/C₂H₅OH, 3 h, 97%; (d) NBS/THF, CH₃COOH, rt. 24 h, 87%; (e) NCS/THF, CH₃COOH, rt., 24 h, 93%; (f) I₂/KI, NAHCO₃, rt., 2 days, 97%; and (g) n-Bu₃SnH, reflux, 48 h, 79%. Reaction conditions of (C): (a) (C₄H₉)₃SnH, benzene, reflux, 4 h, (75) 80%, (77) 73%; (b) DBU, benzene, reflux, 4 h, (78) 41%, (79) 25%.

Scheme 2

Synthesis of flavanone-derived γ-oxa-ε-lactones (82). Reagents and conditions: (a) KOH/MeOH, reflux, 24–48 h, then HCl (2–3 min), 69–94%; (b) CH₃COONa/EtOH, reflux, 48 h, 61–79%; and (c) m-CPBA/CH₂Cl₂, rt., 48 h, 67–90%.

Figure 13

Chemical structure of Nafithromycin (83).

Scheme 3

Synthesis of piperidinol-containing molecule PIPD1 (88) and its analogues (87). Reagents and conditions: (a) K₂CO₃/DCM, rt., 12 h; (b) n-BuLi/Anh., THF, −78 °C then rt., 3 h, 19–95%.

Scheme 4

Synthesis of methyl β-d-galactopyranoside (β-MGP) derivatives. Reagents and conditions: (a) DMF, Et3N, −5 °C, 6 h; and (b) R1 -Cl = several acyl halides, −5 °C to r.t, 6 h, 70–80%.

Figure 14

Structures of amino sugar-based isoquinoline-5,8-diones (94) and naphthoquinones (95) and their halogenated compounds, (96) and (97).

Scheme 5

Synthetic scheme of; (a) 3,5-disubstituted isoxazole (99) and (b) 3,5-disubstituted and 3,4,5-trisubstituted-4,5- dihyroisoxazoles (101). Reagents and conditions: (a) Et₃N, dry THF, reflux, 6–8 h, 80%; and (b) Et₃N, dry C₆H_6, reflux, 8 h, 75–85%.

Scheme 6

Synthesis of isoxazole-acridone derivatives (105). Reagents and conditions: (a) [Cu], K₂CO₃; (b) polyphosphoric acid (PPA), 120 °C; (c) propargyl bromide, K₂CO₃, tetra-n- butylammonium bromide (TBAB) as catalyst (PTC), DMF, rt. 6 h, 75%; and (d) Method 1: Et₃N, chloroform, 50 °C, 6 h; Method 2: Et₃N, chloroform, microwave irradiation (200 W), 40–70 °C, 20–25 min, 45–85%.

Scheme 7

Synthesis of A–33853 antibiotic (113). Reagents and conditions: (a) CDI, THF, reflux, 18 h, 60%; (b) POCl₃, xylene, 140 °C, 3 h, 58%; (c) MeOH, 40 °C, 12 h; (d) DDQ, CH₂Cl₂, r.t, 12 h, 37%; (e) Pd/C, H₂, MeOH, r.t, 12 h, 80%; (f) BnBr, Ag₂O, CH₂Cl₂/DMSO (1:1), r.t, 12 h, 70%; (g) LiOH, THF/ H₂O/MeOH (3:1:1), r.t, 12 h, 94%; (h) (COCl)₂, r.t, 3 h; (i) pyridine, DMAP (cat.), CH₂Cl₂, r.t, 12 h, 34%; and (j) excess BBr3, CH₂Cl₂, −78 °C to r.t, 16 h, 81%.

Scheme 8

Synthetic route of N-alkylcarbazole aminothiazoles (117). Reagents and conditions: (a) alkyl bromide, NaH, dry DMF, rt., 6 h, 96–98%; (b) ClCH₂COCL, AlCl, dry DCM, rt., 24 h, 30–36%; (c) thiourea, ethanol, reflux, 1 h, 94–96%.

Scheme 9

Synthesis of novel series of carbazole derivatives (122, 124 and 126). Reagents and conditions: (a) DMC, DABCO, 95 °C, 24 h, or KOH, 25 °C, 2 h, or NaH, DMF, 25 °C, 16 h; (b) POCl₃, DMF, 90 °C, 8–18 h; (c) AcOH, 120 °C, 4–8 h, 35.1–61.6%; (d) CH₂CH₃OH, HCl, 40 °C, 6 h, or CH₃OH, AcOH, 68 °C, 4 h, 38.7–64.6%; and (e) CH₂CH₃OH, AcOH, 70 °C, 5 h, 64.2–80%.

Scheme 10

Synthesis of pyrimidine amines derivatives with bicyclic monoterpene units: (a) pinanyl pyrimidine amines derivatives. Reagents and conditions: (a) NaOCH₃, or t-BuOK, t-BuOH, reflux 6–24 h, 60.5–85.5%; (b) NaOH, t-BuOH or THF, reflux, 10–30 h, 35.5–82.5%; (c) DIPEA or NaH, THF, 65 °C, 3 h, 40–79.8%; and (b) camphoryl pyrimidine amine derivatives. Reagents and conditions: (2a) t-BuOK, t-BuOH, reflux, 6 h, 56.8%; (2b) NaOH, t-BuOH, reflux, 10 h, 30.8%; and (2c) DIPEA, THF, 65 °C, 3 h, 39.1–73%.

Scheme 11

Synthesis of a series of novel pyrimidine derivatives containing sulfonate esters. Reagents and conditions: (a) NH₂SNH₂, KOH, EtOH 70 °C, 0.5 h, 85–90%; (b) C₂H₅I, K₂CO₃, DMF, rt.; (c) MeI, K₂CO₃, DMF, rt.; (d) benzyl chloride, K2CO3, DMF, rt.; (e) RSO₂Cl, Et₃N, DCM, rt., 12 h, 40–82%; (f) RSO₂Cl, Et₃N, DCM, rt., 12 h, 65%, 69%; (g) RSO₂Cl, Et₃N, DCM, rt., 12 h, 70%, 75%.

Scheme 12

Synthesis of Pyrazole ligand N,N-bis(2(1′,5,5′-trimethyl-1H,1′H- [3,3′-bipyrazol]-1-yl)ethyl)propan-1-amine (L) (140) and bis-pyrazole coordination complexes (141–144). Reagents and conditions: (a) TsCl₂/CH₂Cl₂, 0 °C 5 h, 60%; (b) Propylamine/K₂CO₃/CH₃CN, reflux, 15 days, 30%; (c) CuCl₂.2H₂O, MeOH, diethyl ether, 25 °C, 6 days, 44%; (d) Ni(ClO₄)₂.6H₂O, MeOH, diethyl ether, 25 °C, 8 days, 29%; (e) No(ClO₄)₂.6H₂O, MeOH, diethyl ether, 25 °C, 9 days, 35%; and (f) FeCl₂ then KnCS, EtOH, 25 °C, 6 days, 37%.

Scheme 13

Synthesis of 4-trifluoromethylphenyl-substituted pyrazole derivatives (148). Reagents and conditions: (a) ethanol, reflux, 12 h; (b) POCL₃, DMF, 80 °C, 6h, 97%; and (c) H₂NR, EtOH, Reflux, 8 h, 1.84–20.93%.

Figure 15

Chemical structure of, Cefiderocol (CFDC) (149), siderophore-antibiotic conjugates (150), enterobactin-ciprofloxacin conjugate (151), oxazolidinone-cephalosporin-bis-catechol-based siderophore conjugates (152), piperazine-based siderophore mimetics (153), (154), siderophore-linked ruthenium catalysts (155), moxifloxacin (156), N-moxi (157), C-moxi (158), and cisplatin prodrug-enterobactin (159).

Scheme 14

Procedure for synthesis of carbapenem-oxazolidinone hybrids (163). Reagents and conditions: (a) i-Pr₂NEt, CH₃CN, −10–0 °C, 8 h, 72–81%; and (b) H₂, 10% Pd-C, THF/H₂O, 30 °C, 2 h, 55–76%.

Figure 16

Chemical structure of; JSF-2414 (164); JSF-2659 (165); cephalothin-Bac8c (166); and florfenicol (167).

Figure 17

Chemical structure of WCK 5153 (168), ANT3310 (169), avibactam (170), relebactam (171), nacubactam (172), zidebactam (173), β-Lactamase-Activated Ciprofloxacin Prodrug (174), azithromycin prodrug (CSY5669) (175), tedizolid phosphate (TR701) (176), pretomanid (177), ceftaroline fosamil (178), C3D (179), DEA-C3D (180), triclosan glycoside prodrugs (181), prodrugs of 5-modified 2ʹ-deoxyuridines (182), tebipenem pivoxil HBr salt (183), TXY436 (184), TXA709 (185), carvacrol prodrugs (WSCP18-19) (186), ADC111 (187), ADC112 (188), ADC113 (189), and contezolid acefosamil (CZA) prodrug (190).