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Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity.

Li S, Luan G, Ren X, Song W, Xu L, Xu M, Zhu J, Dong D, Diao Y, Liu X, Zhu L, Wang R, Zhao Z, Xu Y, Li H - Sci Rep (2015)

Bottom Line: Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range.Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo.Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

ABSTRACT
Human dihydroorotate dehydrogenase (hDHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range. Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo. Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold. This work not only elucidates promising scaffolds targeting hDHODH for the treatment of rheumatoid arthritis, but also demonstrates that the water-mediated hydrogen bond interaction is an important factor in molecular design and optimization.

No MeSH data available.


Related in: MedlinePlus

In vivo effects of compound 19 on collagen-induced arthritis (CIA) rats.Arthritis was induced in Wistar rats by twice immunization with type II collagen on day 0 and day 7. Compound 19 was administered i.p. daily at 5 mg/kg and 30 mg/kg until the end of this experiment. Methotrexate, as the positive control, was administered at the dose of 0.3 mg/kg. (A) Measurement of body weight was taken every three days. Treatment of compound 19 or methotrexate had no obvious effect on the growth of body weight versus model group. (B) The incidence and severity of arthritis in different groups were evaluated via observation of the changes of arthritis scores every two days. Compound 19 displayed significant anti-arthritic effect in vivo (p < 0.05) and obviously alleviated foot swelling in a dose-dependent manner. (C) The representative photomicrographs of knee joints in different treatments groups taken after 28 day’s trial. The arthritis swelling of the model group was the worst. The swelling hind paw was obviously relieved in the group treated with compound 19. (D) Representative H & E stained sections of joint tissue of each groups. Compared with model group and compound 19 treated groups, the latter could remarkably alleviate the histological changes of severe arthritis. Asterisk indicates the infiltration of the inflammatory cells; solid triangles indicate areas with synovial degradation; solid arrows indicate areas of cartilage degradation; and the oval highlights the inflammatory cells. S, synovium; C, cartilage; Bn, bone. Magnification = 50 ×. Data was expressed as mean ± SEM. ##P < 0.01 vs normal control, *P < 0.05, **P < 0.01 vs CIA group.
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f5: In vivo effects of compound 19 on collagen-induced arthritis (CIA) rats.Arthritis was induced in Wistar rats by twice immunization with type II collagen on day 0 and day 7. Compound 19 was administered i.p. daily at 5 mg/kg and 30 mg/kg until the end of this experiment. Methotrexate, as the positive control, was administered at the dose of 0.3 mg/kg. (A) Measurement of body weight was taken every three days. Treatment of compound 19 or methotrexate had no obvious effect on the growth of body weight versus model group. (B) The incidence and severity of arthritis in different groups were evaluated via observation of the changes of arthritis scores every two days. Compound 19 displayed significant anti-arthritic effect in vivo (p < 0.05) and obviously alleviated foot swelling in a dose-dependent manner. (C) The representative photomicrographs of knee joints in different treatments groups taken after 28 day’s trial. The arthritis swelling of the model group was the worst. The swelling hind paw was obviously relieved in the group treated with compound 19. (D) Representative H & E stained sections of joint tissue of each groups. Compared with model group and compound 19 treated groups, the latter could remarkably alleviate the histological changes of severe arthritis. Asterisk indicates the infiltration of the inflammatory cells; solid triangles indicate areas with synovial degradation; solid arrows indicate areas of cartilage degradation; and the oval highlights the inflammatory cells. S, synovium; C, cartilage; Bn, bone. Magnification = 50 ×. Data was expressed as mean ± SEM. ##P < 0.01 vs normal control, *P < 0.05, **P < 0.01 vs CIA group.

Mentions: Compound 19 and methotrexate were injected intraperitoneally once per day for 28 days into the Wistar rats with collagen-induced arthritis (CIA). The swelling scores of the arthritis and morphological observations of the rats’ joint tissues were employed to examine the anti-arthritic effect of compound 19 (Fig. 5). With the onset of arthritis, the swelling scores were an indication of the disease states. The maximum score was 8, which is the sum of the scores from both hind paws of each rat and indicates a severe arthritis state. During the experiment, the control rats had normal eating patterns, shiny hair and continuously increasing body weight. By contrast, the rats in the model group exhibited a rough and dull hair at the beginning of the trial, and a slower increase in body weight relative to the normal group after day 9 (Fig. 5A). Although treatment with compound 19 or methotrexate had no obvious influence on increase in body weight, compound 19 displayed significant dose-dependent anti-arthritic effect (p < 0.05) and obviously alleviated foot swelling (Fig. 5B,C). The arthritis scores of the CIA rats reached their peak and stabilized (Fig. 5B) around 8 after day 18, presenting a severe arthritis state, while the arthritis scores of the compound 19 treated rats decreased and were around 5 (5 mg/kg) and 3 (30 mg/kg) at the day 28, which indicated that compound 19 can display substantial anti-inflammation effects and alleviate foot swelling in a dose-dependent manner (Fig. 5B,C).


Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity.

Li S, Luan G, Ren X, Song W, Xu L, Xu M, Zhu J, Dong D, Diao Y, Liu X, Zhu L, Wang R, Zhao Z, Xu Y, Li H - Sci Rep (2015)

In vivo effects of compound 19 on collagen-induced arthritis (CIA) rats.Arthritis was induced in Wistar rats by twice immunization with type II collagen on day 0 and day 7. Compound 19 was administered i.p. daily at 5 mg/kg and 30 mg/kg until the end of this experiment. Methotrexate, as the positive control, was administered at the dose of 0.3 mg/kg. (A) Measurement of body weight was taken every three days. Treatment of compound 19 or methotrexate had no obvious effect on the growth of body weight versus model group. (B) The incidence and severity of arthritis in different groups were evaluated via observation of the changes of arthritis scores every two days. Compound 19 displayed significant anti-arthritic effect in vivo (p < 0.05) and obviously alleviated foot swelling in a dose-dependent manner. (C) The representative photomicrographs of knee joints in different treatments groups taken after 28 day’s trial. The arthritis swelling of the model group was the worst. The swelling hind paw was obviously relieved in the group treated with compound 19. (D) Representative H & E stained sections of joint tissue of each groups. Compared with model group and compound 19 treated groups, the latter could remarkably alleviate the histological changes of severe arthritis. Asterisk indicates the infiltration of the inflammatory cells; solid triangles indicate areas with synovial degradation; solid arrows indicate areas of cartilage degradation; and the oval highlights the inflammatory cells. S, synovium; C, cartilage; Bn, bone. Magnification = 50 ×. Data was expressed as mean ± SEM. ##P < 0.01 vs normal control, *P < 0.05, **P < 0.01 vs CIA group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595849&req=5

f5: In vivo effects of compound 19 on collagen-induced arthritis (CIA) rats.Arthritis was induced in Wistar rats by twice immunization with type II collagen on day 0 and day 7. Compound 19 was administered i.p. daily at 5 mg/kg and 30 mg/kg until the end of this experiment. Methotrexate, as the positive control, was administered at the dose of 0.3 mg/kg. (A) Measurement of body weight was taken every three days. Treatment of compound 19 or methotrexate had no obvious effect on the growth of body weight versus model group. (B) The incidence and severity of arthritis in different groups were evaluated via observation of the changes of arthritis scores every two days. Compound 19 displayed significant anti-arthritic effect in vivo (p < 0.05) and obviously alleviated foot swelling in a dose-dependent manner. (C) The representative photomicrographs of knee joints in different treatments groups taken after 28 day’s trial. The arthritis swelling of the model group was the worst. The swelling hind paw was obviously relieved in the group treated with compound 19. (D) Representative H & E stained sections of joint tissue of each groups. Compared with model group and compound 19 treated groups, the latter could remarkably alleviate the histological changes of severe arthritis. Asterisk indicates the infiltration of the inflammatory cells; solid triangles indicate areas with synovial degradation; solid arrows indicate areas of cartilage degradation; and the oval highlights the inflammatory cells. S, synovium; C, cartilage; Bn, bone. Magnification = 50 ×. Data was expressed as mean ± SEM. ##P < 0.01 vs normal control, *P < 0.05, **P < 0.01 vs CIA group.
Mentions: Compound 19 and methotrexate were injected intraperitoneally once per day for 28 days into the Wistar rats with collagen-induced arthritis (CIA). The swelling scores of the arthritis and morphological observations of the rats’ joint tissues were employed to examine the anti-arthritic effect of compound 19 (Fig. 5). With the onset of arthritis, the swelling scores were an indication of the disease states. The maximum score was 8, which is the sum of the scores from both hind paws of each rat and indicates a severe arthritis state. During the experiment, the control rats had normal eating patterns, shiny hair and continuously increasing body weight. By contrast, the rats in the model group exhibited a rough and dull hair at the beginning of the trial, and a slower increase in body weight relative to the normal group after day 9 (Fig. 5A). Although treatment with compound 19 or methotrexate had no obvious influence on increase in body weight, compound 19 displayed significant dose-dependent anti-arthritic effect (p < 0.05) and obviously alleviated foot swelling (Fig. 5B,C). The arthritis scores of the CIA rats reached their peak and stabilized (Fig. 5B) around 8 after day 18, presenting a severe arthritis state, while the arthritis scores of the compound 19 treated rats decreased and were around 5 (5 mg/kg) and 3 (30 mg/kg) at the day 28, which indicated that compound 19 can display substantial anti-inflammation effects and alleviate foot swelling in a dose-dependent manner (Fig. 5B,C).

Bottom Line: Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range.Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo.Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

ABSTRACT
Human dihydroorotate dehydrogenase (hDHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range. Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo. Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold. This work not only elucidates promising scaffolds targeting hDHODH for the treatment of rheumatoid arthritis, but also demonstrates that the water-mediated hydrogen bond interaction is an important factor in molecular design and optimization.

No MeSH data available.


Related in: MedlinePlus