Synthesis, pharmacological evaluation and structure-activity relationship of recently discovered enzyme antagonist azoles

Abstract

Global people are suffering from the legion of diseases. Cytotoxic property of the chemical compound would not solely influence effective drug properties and reduce unnecessary side effects. Proteins/enzymes responsible for microbe proliferation or survival are specifically targeted and inhibited successfully making the cells to undergo apoptosis. Furthermore, isoforms of essential enzymes have distinct physiological functions; thereby inhibition of essential enzyme isoforms is an apt way to the clinical approach of disease neutralization. Drugs are designed so as to play significant roles such as signaling pathways in the oncogenic process including cell proliferation, invasion, and angiogenesis. The present review comprises collective information of the recent synthesis of various organic drug compounds in brief, which could inhibit particular enzyme. The review also covers the correlation of the structure of a drug molecule designed and its inhibitory activity. Also, the most significant enzyme inhibitors are highlighted and structural moieties/core units responsible for remarkable inhibitory values are emphasized.

Keywords: COX; Carbonic anhydrase; Enzyme inhibitors; Natural product chemistry; Organic chemistry; Pyrazole; Thiazole.

Scheme 1

Synthesis of dual c-Met and VEGFR-2 inhibitors [1]; Reagents and conditions: (a) LiOH, MeOH/H₂O, rt. 1h; (b) EDC, HOBt, DCM, aniline or substituted aniline; (c) LiOH, MeOH/H₂O, rt.; (d) EDC, DMA, substituted or unsubstituted 4-aminophenol; (e) K₂CO₃, isopropanol.

Figure 1

Structures of most potent dual c-Met and VEGFR-2 inhibitors.

Scheme 2

Synthetic route for preparation of 1,2,3-1H-triazoles derivatized 4H-pyrano [2,3-d] pyrimidine analogs [2]; Reagents and conditions: (a) Ammonium solution 25%, 25 °C, 3 h, or Cu@MOF-5 (10 mol%), 96% EtOH, 50 °C, 1 h; (b) Acetic anhydride, Conc. H2SO4 (cat.), 15 min, in refluxing, then 25 °C, 24 h; (c) Propargyl bromide, anhydrous potassium carbonate, dry acetone, in refluxing, 4–5 h; (d) Cu@MOF-5 (cat.), 79–80 °C, abs. EtOH, 4–5 h.

Figure 2

Illustration of structures of remarkable MTB PtpB inhibitors.

Scheme 3

Synthesis of compounds 18a-e [3]; Reagents and conditions: i. absolute ethanol, NaOEt/1-bromoheptane, reflux; ii. 4-X-salicylaldehyde, 160–165 °C, oil bath heating; iii. H₃PO₂ solution, NaNO₂, room temperature; iv. absolute ethanol, NaOEt/ethyl bromoacetate, reflux; v. butanol, NH₂NH₂・H₂O, reflux; vi. ethanol, 4-X-salicylaldehyde, reflux.

Figure 3

Structure of 1,2,4-triazole-5-one derivative with significant CA II inhibitory activity.

Scheme 4

Synthesis of 1,2,4-triazole-based benzothiazole/benzoxazole derivatives (27a-n) [4]; Reagents and conditions: i) Conc. H₂SO₄, ethanol; ii) NH₂NH₂.H₂O, Abs. ethanol; iii) 8% w/v NaOH; iv) Anhyd. K₂CO₃, acetone.

Figure 4

Structures of 1,2,4-triazole derivatized benzothiazoles/benzoxazoles possessing noteworthy p38α MAB kinase inhibitory activities.

Scheme 5

Synthesis of intermediate compounds 29a-d; Reagents and conditions; i) acetic anhydride, fused sodium acetate (100 °C).

Scheme 6

Synthetic route for the preparation of final compounds 30a-l [5]; Reagents and conditions; i) glacial acetic acid, fused sodium acetate, water bath (100 °C).

Scheme 7

Synthesis of target compounds 31a, b and 33a-f [5]; Reagents and reaction conditions: i) glacial acetic acid, fused sodium acetate, water bath, (100 °C); ii) K₂CO₃, DMF, rt stir (30 min), 5a-c (100 °C).

Figure 5

Structure of significant p38αMAPK inhibitor 30h and p38αMAPK inhibitor/CA dual inhibitor 31a.

Scheme 8

Synthesis of target compounds 41a, b and 42 [6]; Reagents and conditions: (i) Hydrazine hydrate, EtOH, 60 °C; (ii) glacial AcOH, NaOAc, chloroacetyl chloride, RT; (iii) Benzene, 83 °C; (iv) POCl₃, 110 °C; (v) piperazine, MeOH, reflux; (vi) TEA, THF, reflux; (vii) piperazine, TEA, THF, 60 °C.

Scheme 9

Synthetic route for preparation of final compounds 49 and 51 [6]; Reagents and conditions: i) POCl₃, 110 °C; ii) piperazine, MeOH, reflux; iii) TEA, THF, reflux.

Scheme 10

Synthesis of pyrazolo-pyridine derivatives 52–54 [6]; Reagents and conditions: Piperazine analogs, THF, 65 °C.

Scheme 11

Synthetic route for design of 2,4,5-trisubstituted-1,2,4-triazole-3-one scaffolds [7]; Reagents and conditions: i) absolute ethanol, NaOEt/1-bromoheptane, reflux; ii) H₃PO₂ solution, NaNO₂, room temperature; iii) NaOEt/substituted benzyl bromides.

Scheme 12

Schematic representation of the design of the target compounds 58a-f and 59a-f [8]; Reagent and reaction conditions: i) CDI, Acetonitrile, r.t. 3 h; ii) CDI, Acetonitrile, r.t. 3 h, then reflux 24 h.

Figure 6

Illustration of the structure of most potent LOX inhibitor (58a) and COX-2 inhibitor (58c).

Scheme 13

Design and synthesis of multi-tyrosine kinase inhibitors [9]; i) substituted 4-nitrophenol or 4-nitro-1-naphthol, PhCl, reflux; ii) Fe, Conc. HCl, 95% EtOH–H₂O, reflux; iii) phenyl carbonchloridate, CH₂Cl₂, pyridine, rt; iv) 80% NH₂NH₂·H₂O, xylene, 70 °C; v) 2,6-difluorobenzaldehyde, i-PrOH, HOAc, reflux; vi) SiCl₄, mercaptoacetic acid, CH₂Cl₂, reflux.

Scheme 14

Synthetic route for the preparation of the compounds 66a-c [9]; Reagents and conditions: i) SiCl₄, 2-methylmercaptoacetic acid, 3-mercaptopropionic acid or 2, 2-dimethyl-mercapto acetic acid, CH₂Cl₂, reflux.

Scheme 15

Synthesis of the thiourea derivative 66d [9]; Reagents and conditions: i) CSCl₂, NaHCO₃, H₂O, rt; ii) 80% NH₂NH₂·H₂O, CH₂Cl₂, rt; iii) 2,6-difluorobenzaldehyde, i-PrOH, HOAc, reflux; iv) SiCl₄, mercaptoacetic acid, CH₂Cl₂, reflux.

Scheme 16

Synthesis of compounds 78a-j and 79a-c; Reagents and conditions [9]: i) amine, CH₃CN, reflux; ii) POCl₃, reflux; iii) 2, 6-difluoro-4-nitrophenol, PhCl, reflux; iv) Fe, Conc. HCl, 95% EtOH–H₂O, reflux; v) phenyl carbonochloridate, CH₂Cl₂, pyridine, rt; vi) 80% NH₂NH₂·H₂O, xylene, 70 °C; vii) 2,6-difluorobenzaldehyde, i-PrOH, HOAc, reflux; viii) SiCl₄, mercaptoacetic acid or 3-mercaptopropionic acid, CH₂Cl₂, reflux.

Figure 7

Structure of potent multi-tyrosine kinase inhibitor.

Scheme 17

Synthetic route for the preparation of the final compounds 84a-g [10]; Reagents and conditions: i) bromoethylacetate, K₂CO₃, acetone; ii) NH₂NH₂•H₂O, EtOH, reflux; iii) R-CNS, EtOH, reflux; iv) 2N NaOH/1M NaHCO₃.

Figure 8

Structures of the remarkable urease inhibitors.

Scheme 18

Synthetic pathway for the preparation of the compounds 90 and 91 [11]; Reagents and conditions: i) SOCl₂, dry CH₂Cl₂, rt (10 min), 80 °C (2.5–3h); ii) tBu-NH₂, dry CH₂Cl₂, 80 °C (12h); iii) SO₂Cl₂, ClCH₂CH₂Cl, rt (24h); iv) m-CPBA (1.4 eq), CH₂Cl₂; v) m-CPBA (3.0 eq).

Scheme 19

Synthetic route for preparation of target 5-arylisothiazole oxide scaffolds; Reagents and conditions: i) Ar-B(OH)₂ (2.0 eq), K₂CO₃ solid, 80 ˚C/GPA: Pd(PPh₃)₄, THF or GPA: PdCl₂(dppf), CH₂Cl₂, DME, sealed tube; ii) TFA, MW, sealed tube.

Figure 9

Structures of 5-arylisothiazoles as most significant CA IX and XII inhibitors.

Figure 10

Structure of potent lanosterol-14α-demethylase inhibitor.

Scheme 20

Illustration of synthetic route for preparation of compounds 101a-b [13]; Reagents and conditions: i) benzyl bromide, DMF, reflux (2h); ii) NH₂NH₂, rt (15 min); iii) CS₂, KOH, EtOH, reflux (6h); iv) benzyl bromide and or ethyl iodide, EtOH, KOH, rt (2h); v) EtOH, CS₂, KOH, rt (14h); vi) NH₂NH₂, reflux (1h); vii) Ar-CHO, AcOH, reflux (20min).

Scheme 21

Representation of design of compounds 107 and 108 [13]; Reagents and conditions: i) Isopropyl iodide, DMF, reflux, (2h); ii) NH₂NH₂, rt (2h); iii) benzoylacetoacetate and/or benzoyl acetone, EtOH, AcOH, reflux (12h).

Scheme 22

Synthesis of the final compounds 111 and 112a-c [13]; Reagents and conditions: i) diethyl 2-bromomalonate, DMF, reflux (2h); ii) NH₂NH₂, rt (20min); iii) benzoyl acetone, EtOH, AcOH, reflux (12h); iv) Ar-CHO, EtOH, AcOH, reflux (2h).

Figure 11

Structure of compound 112a possessing COX-1 inhibitory.

Scheme 23

Preparation of target compounds 114a-j and 115a-j [14].

Scheme 24

Synthetic route for the preparation of the compounds 117a-b and 118a-b [14].

Scheme 25

Schematic representation of compounds 119a-g and 120a-g [14].

Figure 12

Structures of potent CA inhibitors.

Scheme 26

Illustration of the structures of carbazole and hydrazone-bridged thiazole-pyrazole derivatives [18].

Scheme 27

Synthesis of carbazole-imidazole derivatives 127a-w [19]; Conditions and reagents: i) TFA (70%), CHCl₃, 50 °C (1h); Ar'CHO, NH₄OAc, 80 °C (8h).

Figure 13

Representation of carbazole-imidazole derivatives as potent α-glucosidase inhibitors.

Scheme 28

Synthesis of the target molecules 132a-t [20]; Reagents and conditions: i) Conc. H₂SO₄, 0–10 °C (2–3h); ii) ethyl bromoacetate, K₂CO₃, acetone, reflux (6h); iii) NH₂NH₂•H₂O, THF, reflux (4h); iv) CS₂, NaOH, EtOH, reflux (12h); v) R-X, K₂CO₃, acetone, reflux (3–5h).

Figure 14

Structures of remarkable CA XII inhibitors.

Scheme 29

Synthetic route for the synthesis of the derivatives 135a-c and 137a-c [21]; Reagents and conditions: i) Arylthioamides, dry DMF, 140 °C; ii) 1M NaOMe, MeOH, rt; iii) Carboxamidines, 4 Eq. K₂CO₃, THF-H₂O (4:1), rt.

Scheme 30

Synthesis of the glucopyranosyl azole derivative 140 [21]; Reagents and conditions: i) 4 Eq. K₂CO₃, THF-H₂O (4:1), rt; ii) 40 Eq. EtSH, 20 Eq. BF₃.Et₂O, dry CH₂Cl₂, rt.

Figure 15

Structures of remarkable GPase inhibitors.

Scheme 31

Synthesis of the diarylpyrazoles 155a-v [22]; Reagents and conditions: i) dimethyl oxalate, MeOH, reflux (6h); ii) 4-hydrazonyl benzenesulfonamide, MeOH, reflux (6H); iii) KOH, MeOH, reflux (2h); iv) EDC•HCl, HOBt, DMAP, CH₂Cl₂, 0 °C, Revitalite, 0.5h.

Scheme 32

Synthetic route for preparation of final compounds 147a-s [22]; Reagents and conditions: i) EDC•HCl, HOBt, DMAP, CH₂Cl₂, 0 °C, Revitalite, 0.5h, RT, overnight.

Figure 16

Structures of pyrazole benzenesulfonamides as COX-2 and 5-LOX inhibitors.

Scheme 33

Synthetic route for preparation of final compounds 155a-x [23]; Reagents and conditions: i) 4-methoxy-benzenemethanol, p-Toluenesulfonic acid, acetonitrile, 60 °C (8h); ii) Potassium cyanate, AcOH, H₂O, 60 °C (5h); iii) Xylene, reflux (8h); iv) Cyclopropylacetylene, n-BuLi, tetrahydrofuran, -50 °C (1h); v) ceric ammonium nitrate, acetonitrile, H₂O, rt (4h); vi) POCl₃, reflux (9h); vii) ArNH₂, n-BuOH, reflux (5–8h).

Figure 17

Illustration of the structure of potent RTase inhibitor.

Scheme 34

Synthesis of quinazoline derivatives 168a-l [24]; Reagents and conditions: i) CH₃I, KHCO₃, DMF, overnight, rt; ii) BnCl, K₂CO₃, KI, 60 °C; iii) AcOH/HCl, 45 °C (8h); iv) CH₂Br₂, K₂CO₃, DMF, 70 °C; v) Pd/C, H₂, EtOH, rt; vi) R₁X, K₂CO₃, DMF, 70 °C; vii) HNO₃/AcOH, 0 °C; viii) Pd/C, H₂, EtOH; ix) formamidine acetate, EtOH, reflux; xi) POCl₃, reflux; xii) triphosgene, THF, triethylamine, 0 °C; xii) K₂CO₃, isopropanol, reflux.

Figure 18

Demonstration of the structure of compound 168j as potent VEGFR-2 inhibitor.

Scheme 35

Synthetic route for the preparation of compounds 174a-p and 175 [25]; i) NaN₃, DMF, rt (12h); ii) L-sodium ascorbate, copper sulfate pentahydrate, EtOH, H₂O, rt; iii) dioxane, H₂O, pd(pddf)Cl₂, K₂CO₃, reflux; iv) 0 °C, CH₂Cl₂, triethylamine, 30min, cyclopropyl carbonyl chloride, rt.

Figure 19

Structures of potent tyrosine kinase inhibitors.

Scheme 36

Synthetic route for the preparation of hydroxyazole derivatives [26]; Reagents and conditions: i) H₂, Pd/C, dry THF; ii) 2,2-diphenylethanamine, 60 °C; iii) a) NaH, MeOH; b) 2M H₂SO₄; iv) benzylamine, 60 °C; v) HBTU, 4-(dimethylamino)pyridine (DMAP), 2,2-diphenylethanamine, dry DMF.

Scheme 37

Synthesis of the derivatives 188a-f [26]; Reagents and conditions: i) Cs₂CO₃, BOC anhydride, dry THF, reflux; ii) NBS, benzoyl peroxide, dichloroethane, reflux; iii) R-(Ph)-XH, Cs₂CO₃, dry DMF; iv) TFA, DCM; v) 5M NaOH, EtOH.

Scheme 38

Preparation of the final compounds 192a-c and 194 [26]; Reagents and conditions: i) R₁X, K₂CO₃, acetonitrile; ii) 5M NaOH, EtOH; iii) a) oxalyl chloride, dry DMF, dry THF, 0 °C; b) aq NH₃, THF; iv) H₂, Pd/C, dry THF.

Figure 20

Structure of compound 190e possessing efficient pfDHODH inhibitory activity.

Scheme 39

Synthetic route for the preparation of thiazole derivatives 199a-z and 200a-d [27]; Reagents and conditions: i) PdCl₂(PPh₃)₂, ethylnyltrimethylsilane (2 Equiv), 50 °C (24h); ii) iii) PdCl₂(PPh₃)₂ (5% mol), CuI (7.5% mol), Et₃N for 6–24h; iv) aminoguanidine HCl, EtOH.

Figure 21

Demonstration of structures of most significant inhibitors.

Scheme 40

Strategic design and synthesis of the pyrazole-benzenesulfonamide derivatives [28]; Reagents and conditions: i) Chloroalkanecarbonyl chloride, DMF, rt (24h); ii) Morpholine, anhyd. K₂CO₃, DMF, 80 °C (16 h); iii) Acetyl chloride or benzoyl chloride, pyridine, 80 °C, (24h); iv) Aromatic aldehyde, glacial acetic acid, reflux (8–24h).

Figure 22

Structures of most potent COX inhibitors.

Scheme 41

Synthesis of phthalimide-triazoles as COX inhibitors [29]; Reagents and conditions: i) K₂CO₃, DMF, 80 °C (2h); ii) NaN₃, H₂O/t-BuOH, NEt₃; ii) intermediates 209a-m, CuI.

Figure 23

Structures of remarkable tyrosinase inhibitors.

Scheme 42

Design and synthesis of the compounds 212a-d [30]; Reagents and conditions: i) 4-substituted C₆H₅COCH₃; ii) POCl₃/DMF.

Scheme 43

Synthetic route for the preparation of the compounds 214a-d and 215a-d [30]; Reagents and conditions: i) Dry dioxane, piperidine (catalyst) ii) Dry dioxane, CH₃COONH₄ (catalyst).

Scheme 44

Synthesis of the purine-pyrazolothiazoles 216a-h and 217a-h [30]; Reagents and conditions: i) N-substituted thiosemicarbazide, dry dioxane, glacial acetic acid (catalyst), reflux; ii) dry dioxane, anhyd. CH₃COONa, reflux; iii) dry dioxane, anhyd. CH₃COONa, reflux.

Figure 24

Demonstration of the structure of significant 15-LOX inhibitor.

Scheme 45

Strategic design and synthesis of final compounds 221a-g and 222a-c [31]; Reagents and conditions: i) Na, CH₃OH, phenyl isothiocyanate, reflux 1/2 h, cool; ii) Hydrazine hydrate, reflux 1 h; iii) Aryl amine, triethyl orthoformate, DMSO, Oil Bath, 2.5–4.5 h, iv) Aromatic aldehyde, sodium acetate, AcOH, reflux 6 h.

Scheme 46

Synthesis of the pyrazolopyrimidines 226a-d [31]; Reagents and conditions: i) KOH, DMF, phenyl isothiocyanate, stirring, RT, 24 h; ii) Dimethyl sulfate, stirring, RT, 8 h, iii) Hydrazine hydrate, 3–4 h, iv) Hydrochloric acid, aromatic aldehyde, ethyl acetoacetate, ethanol, reflux, 4–8 h.

Scheme 47

Synthetic design and preparation of final compounds 229a-e [31]; Reagents and conditions: i) KOH, DMF, phenyl isothiocyanate, stirring, RT, 24 h; ii) Dimethyl sulfate, stirring, RT, 8 h, iii) Hydrazine hydrate, 3–4 h, iv) Hydrochloric acid, aromatic aldehyde, ethyl acetoacetate, ethanol, reflux, 4–8 h.

Figure 25

Structure of most promising CDK2 inhibitor.

Scheme 48

Design and synthesis of the target compounds 233a-o [32]; Reagents and conditions: i) stirring at room temperature ii) substituted aromatic aldehydes, malononitrile, piperidine, 2 h iii) substituted aromatic aldehydes, EtOH, AcOH, 3 h, Reflux.

Figure 26

Illustration of structures of molecules with remarkable COX-1 inhibitory activity.

Scheme 49

Design and synthesis of fused pyrazole scaffolds [33]; Reagents and conditions: i) SOCl₂, reflux (5h); ii) NH₃, xylene, reflux (5h); iii) SOCl₂+DMF, rt (10h); iv) NH₂NH₂, reflux (5h); vi) NH₂NH₂, toluene, reflux (5h); vii) SOCl₂+DMF, rt (12h); viii) R₁NH₂, reflux (48h).

Figure 27

Illustration of structures of molecules possessing hCA and AChE inhibitory activities.

Scheme 50

Synthetic route for the design of preparation of compounds 245aa-ad [34]; Reagents and conditions: i) Methanol, 2-naphthol, 2-aminobenzothiazole reflux (5h).

Figure 28

Demonstration of significant topoisomerase I inhibitors.

Scheme 51

Synthesis of final compounds 248a-f [35]; Conditions and reagents: i) HCl/H₂O, reflux (3h); ii) substituted benzene diazonium chlorides, EtOH, CH₃COONa.

Scheme 52

Synthetic route for the preparation of the molecules 249a-l [35]; Reagents and conditions: i) HCHO/EtOH, stirring, 60 °C (6h).

Scheme 53

Design and synthesis of the pyrazole derivatives 250a-f [35]; Reagents and conditions: i) CH₃COONH₄, EtOH, reflux (15h).

Figure 29

Demonstration of structures of excellent COX-2 inhibitors.

Scheme 54

Preparation of pyrazole-thiophene derivatives [36]; Reagents and conditions: i) NH₂NH₂.H₂O, EtOH, reflux (5h); ii) EtOCH=C(COOEt)₂, Anhyd.K₂CO₃, EtOH, reflux (6h); iii) EtOCH=C(CN)COOEt, Anhyd.K₂CO₃, EtOH, reflux (6h); iv) EtOH, reflux (12h); v) CH₃COCH₂COCH₃, EtOH, reflux (10h).

Scheme 55

Synthesis of fused thiophene-pyrimidine incorporated pyrazole derivatives [36]; Reagents and conditions: i) NH₂NH₂.H₂O, reflux (1h); ii) EtOCH=C(CN)_2, Anhyd.K₂CO₃, EtOH, reflux (6h); iii) EtOCH=C(CN)COOEt, Anhyd.K₂CO₃, EtOH, reflux (6h); iv) EtOCH=C(COOEt)₂, Anhyd.K₂CO₃, EtOH, reflux (12h); v) CH₃COCH₂COCH₃, EtOH, reflux (10h); vi) EtOH, reflux (6h); vii) Anhyd. CH₃COONa, Br₂ in AcOH, stir (overnight).

Figure 30

Structures of remarkable COX-2 inhibitors.

Scheme 56

Synthesis of dihydropyrazole-benzenesulfonamide derivatives [37]; Reagents and conditions: i) EtOH, aq. NaOH (20%), rt. ii) p-hydrazinobenzene sulfonamide hydrochloride, EtOH, glacial acetic acid, reflux (4–19h).

Figure 31

Structures of remarkable hCA inhibitors.

Scheme 57

Synthetic pathway for preparation of compounds 275a-b [38]; Reagents and reaction conditions: i) phenylhydrazine hydrochloric (R = H) and p-methane sulfonyl hydrochloride (R = SO₂CH₃), sodium acetate, 95% ethanol, reflux (5h); ii) formic acid (85%), reflux (10h); iii) POCl₃, DMF, reflux (4h); iv) glycine ethyl ester hydrochloride, TEA, absolute ethanol, reflux (5–6h); v) hydrazine hydrate, EtOH, reflux (10h).

Scheme 58

Synthesis of the pyrazolo-pyrimidine derivatives [38]; Reagents and conditions: i) appropriate aldehyde, absolute EtOH, gl. Acetic acid, reflux (4h); ii) ethyl isothiocyanate, absolute ethanol, TEA, reflux (3h); iii) appropriate phenyl or 4-substituted phenyl isothiocyanate, absolute ethanol, TEA, reflux (3h).

Scheme 59

Preparation of target molecules 279a, b and 280a, b [38]; Reagents and conditions: i) CS₂, KOH, absolute ethanol, reflux (3h); ii) ethyl acetoacetate, absolute ethanol, reflux (10h).

Scheme 60

Synthesis of the target molecules 284a-n [39]; Reagents and conditions: i) AcOH, EtOH, 70 °C; ii) a. DMF, POCl₃, 0→70 °C (3h); b. aq NaOH/aq NaHCO₃; iii) DCM/MeOH (8:1), EDA (0.2 mmol), AcOH (2 mM).

Figure 32

Representation of structures of potent alkaline phosphatase/nucleotide pyrophosphatase inhibitors.

Scheme 61

Preparation of the compounds 292a-b [40]; Reagents and conditions: i) NaH, 4-methoxybenzyl chloride, DMF, 0 °C, rt, (18h); ii) NaHMDS, ethyl 4-fluorobenzoate, THF, 0 °C, rt, (2h); iii) NaNO₂, AcOH, rt, (1h); iv) H₂, Pd/C, methanolic HCl, 45 °C, (6h); v) KSCN, DMF, 160 °C (2h); vi) CH₃I, NaOtBu, MeOH, 55 °C (2h); (in case of preparation of 292a) or benzyl bromide, Cs₂CO₃, DMF, rt (36h) (in case of preparation of 292b); vii) TFA, 45 °C.

Scheme 62

Synthetic route for preparation of compounds 295a-u [40]; Reagents and conditions: i) carboxylic acid, PyBOP, DIPEA, DCM, rt; ii) carboxylic acid, HATU, DIPEA, DCM, rt; iii) acyl chloride, pyridine, 0 °C, rt; iv) amide, Pd₂(dba)₃, XantPhos, Cs₂CO₃, DMF, 100 °C (16h); v) H₂O₂, MeCN, rt.

Scheme 63

Design and synthesis of compound 299 and 300 [40]; Reagents and conditions: i) cyclopropanecarbonyl chloride, pyridine, 0 °C, rt (2h); ii) cyclopropanecarboxamide, Pd₂(dba)₃, XantPhos, Cs₂CO₃, DMF, 100 °C (16h).

Scheme 64

Preparation of the compounds 305a-g [40]; Reagents and conditions: i) SeO₂, acetic acid, 130 °C, 1.5h; ii) TFA, rt; iii) cyclopropanecarbonyl chloride, DIPEA, DCM, rt (18h); iv) R-CHO, NH₄OAc, acetic acid, 130 °C (3–4h).

Scheme 65

Synthetic route for the preparation of pyridineimidazole derivative 310 [40]; Reagents and conditions: NaH, 2-(trimethylsilyl)ethoxymethyl chloride, THF, 0 °C, rt (18h); ii) n-butyllithium, tributyltin chloride, Et₂O, 0 °C, rt (2h); iii) N-(4-bromopyridin-2-yl)cyclopropanecarboxamide, Pd(PPh₃)₄, 1,4-dioxane, 105 °C (18h); iv) TFA, DCM, rt (6h).

Figure 33

Illustration of structures of noteworthy GSK3β/p38α MAP kinase inhibitors.

Scheme 66

Design and synthesis of quinazolinone moiety linked to thiadiazole derivatives [41]; Reagents and conditions: i) BrCH₂COOC₂H₅, K₂CO₃, acetone; ii) NH₂NH₂•H₂O, EtOH; iii) C₂H₅NCS, EtOH, reflux; iv) 1M NaHCO₃, reflux; v) dil. H₂SO₄.

Scheme 67

Synthesis of compound quinoline derivative 319 [42]; Reagents and conditions: i) NaOH, CH₃COC₆H₄CH₃, RT (4h); ii) gl. AcOH, reflux (10h).

Scheme 68

Synthetic pathway for the design of the quinoline-dihydropyrazole analogs [42]; Reagents and conditions: i) NH₂NHC=XNH₂, NaOH, EtOH, reflux (12h); ii) NH₂NH₂•H₂O, AcOH, reflux (20h).

Scheme 69

Synthetic route for the design of the pyrazole-thiazole linked quinolones [42]; Reagents and conditions: i) substituted phenacyl bromide, EtOH, reflux (4h); ii) appropriate 3-chloropentane-2,4-diones, EtOH, reflux (4h); iii) appropriate 2-oxo-N-arylpropanehydrazonyl chloride, EtOH, reflux (4h).

Figure 34

Structure of potent EGFR inhibitor.

Scheme 70

Preparation of benzo[d]imidazole-quinoline derivatives [43]; Reagents and conditions: i) N-phenyl-bis(trifluoromethanesulfonimide), rt (2d); ii) tris(dibenzylideneacetone) dipalladium(0), cesium carbonate, rac-BINAP, reflux (3d); iii) TFA.

Scheme 71

Synthetic route for the preparation of compounds 327a-b [43]; Reagents and conditions: i) R-OMs, Cesium carbonate, reflux, overnight; ii) TFA.

Scheme 72

Synthesis of radioiodinated compound [¹²⁵I] 333 [43]; Reagents and conditions: i) NCS, NaI, 50 °C, overnight ii) Boc₂O, TEA, rt (3d) iii) hexabutyldistannane, Pd[P(C₆H₅)₃]₄, reflux (24h) iv) [¹²⁵I]NaI, NCS, acetic acid, rt (15min) v) TFA, rt (30min).

Scheme 73

Synthetic pathway for preparation of radioiodinated compound 336 [43]; Reagents and conditions: i) i) NCS, NaI, 50 °C, overnight ii) hexabutyldistannane, Pd[P(C₆H₅)₃]₄, reflux (48h) iii) [¹²⁵I]NaI, NCS, acetic acid, rt (15min).

Figure 35

Representation of structures of molecules with strong PDGFRβ affinity.

Scheme 74

Synthetic way for the preparation of the thiazolo-benzene sulfonamides [44]; Reagents and conditions: i) SOCl₂, reflux (12hr); ii) NaN₃/Ice bath/stirring (2hr); iii) Dry toluene/reflux (1hr); iv) Dry toluene/reflux (4hr).

Scheme 75

Synthesis of the final compounds 346a-d and 347a-d [44]; Reagents and conditions: i) SOCl₂/DMF, reflux (5hr); ii) NaN₃/Ice bath/stirring (2hr); iii) Dry toluene/reflux (1hr); iv) Dry toluene/reflux (4hr).

Figure 36

Representation of significant CA inhibitory molecules.

Scheme 76

Solid-phase synthesis of tetrazole-peptidomimetics by Ugi-azide reaction [45].

Figure 37

Demonstration of structures of significant ePepN inhibitors.

Scheme 77

Synthetic route for the preparation of the compounds 354a-j [46]; Reagents and conditions: i) NH₂CSNHNH₂, EtOH, reflux (12h); ii) RCOCH₂Br, EtOH, reflux (6h).

Figure 38

Illustration of structures of potent Akt inhibitors.

Scheme 78

Synthetic route for the preparation of thiazol-hydrazolo-coumarin derivatives [47]; Reagents and conditions: i) EtOH, Anhyd. CH₃COONa, CH₃COCH₂Cl, reflux; ii) EtOH, Anhyd. CH₃COONa, Phenacyl bromide, reflux; iii) EtOH, Anhyd. CH₃COONa, 4-Bromo phenacyl bromide, reflux; iv) EtOH, Anhyd. CH₃COONa, 2-bromoacetyltetralin, reflux; v) EtOH, Anhyd. CH₃COONa, 3-chloroacetylacetone, reflux; vi) EtOH, Anhyd. CH₃COONa, ethyl-2-chloroacetoacetate, reflux; vii) EtOH, Anhyd. CH₃COONa, ethyl bromoacetate, reflux.

Figure 39

Demonstration of potent anti-proliferative (Hela) and anti-CDK2 inhibitory compound.

Scheme 79

Synthesis of a series of thiazolidine-2,4-dione-azole derivatives [48]; Reagents and conditions: i) H₂O, Conc. HCl, reflux (10h); ii) K₂CO₃, DMF, 100 °C (5h); iii) piperidine, PhCOOH, 100 °C (1h).

Scheme 80

Synthetic route for the design of pyrrolo-pyridine derivatives [48]; Reagents and conditions: i) Bromoethylacetoacetate, K₂CO₃, DMF, 100 °C (30 min); ii) HCl/CH₃COOH; iii) Pd(dba)₃ Xanthophos, CsCO₃, dioxane, 100 °C (1h).

Figure 40

Structures of thiazolidine-2,-4-dione-azole derivatives with significant α-amylase & α-glucosidase inhibitory percentages.

Scheme 81

Preparation of final compounds 375a & b, 376a & b and 377a & b [49]; Reagents and conditions: i) NH₂CSNHNH₂, EtOH, HCl, reflux; ii) CH₃COCH₂Cl, CH₃COONa, EtOH, reflux; iii) PhCOCH₂Br, CH₃COONa, EtOH, reflux; iv) CH₃COCH(Cl)COOC₂H₅, CH₃COONa, EtOH, reflux.

Scheme 82

Synthetic route for the design of the compounds 378a & b and 379a & b [49]; Reagents and conditions: i) BrCH₂COOC₂H₅, CH₃COONa, EtOH, reflux; ii) CH₃CH(Br)COOC₂H₅, CH₃COONa, EtOH, reflux.

Scheme 83

Synthesis of the compounds 380a,b [49]; Reagents and conditions: i) CH₃CO(Cl)C=NNHAr, Dioxane, Et₃N, reflux.

Scheme 84

Design and preparation of compounds 381a, b [49]: Reagents and conditions: i) ArN₂Cl, EtOH, CH₃COONa•3H₂O.

Figure 41

Demonstration of structures of potent molecules with anti-proliferation/VEGFR-2 activity.

Figure 42

Structures of tropinone derivatives having anticancer properties.

Scheme 85

Design and synthesis of tropinone derivatives 386a-h [50]; Reagents and conditions: i) H₂NNHCSNH₂, AcOH, EtOH, reflux (20h); ii) p-substituted phenacyl bromide EtOH, reflux (20h); iii) H₂NNHCSNH₂, p-substituted phenacyl bromide EtOH, reflux.

Figure 43

Illustration of tropinone-thiazole derivatives as potent tyrosinase inhibitors.