Antitussive and Anti-inflammatory Dual-active Agents Developed from Natural Product Lead Compound 1-Methylhydantoin

Abstract

Natural products play an important role in drug discovery. This work employed a natural product 1-methylhydantoin as the lead compound to develop novel dual-active drugs. 1-Methylhydantoin was isolated from Oviductus Ranae, which is a traditional Chinese medicine that has been used for tussive and inflammation treatment for a long time. An in silico study screened the more active 1-methylhydantoin derivatives. Antitussive assessment indicated that the newly synthesized agent had similar bioactivity with the natural product. An anti-inflammatory model used xylene induced ear edema model. At the same dosage (100 mg/Kg), the newly prepared agent had an inhibition rate 53.18% which was much higher than that of the lead compound (22.69%). The results might be ascribed to the cyclooxygenases-1 (COX-1) and cyclooxygenases-2 (COX-2) selectivity, and the fitness of the compound, and the binding pocket. The anti-particulate matter (PM 2.5) acute pneumonia was evaluated through an in vivo model constructed by nasal instillation with PM 2.5 suspension. The results of the above models suggested that this novel agent had remarkable antitussive, anti-inflammatory, and anti-PM 2.5 acute pneumonia activities.

Keywords: 1-methylhydantoin; Oviductus Ranae; acute pneumonia; anti-inflammatory; antitussive; dual-active; natural product.

Figure 1

Examples used natural product (NP) resources in drug discovery. (a) Aspirin was developed from natural product salicin. (b) Codeine was prepared using morphine as the lead compound. (c) The anticancer drug paclitaxel was isolated from yew. (d) and (e) Penicillin G and quinine were isolated from Penicillium and Cinchona respectively. (f) The strategy of developing dual-active agents using a natural product lead compound 1-methylhydantoin.

Figure 2

Optimization of lead compound 1-methylhydantoin (1-MHD). The hydrophobic moieties were selected from nonsteroidal anti-inflammatory drugs. The designed 1-MHD derivatives were ibuprofen conjugated 1-MHD (1), aspirin conjugated 1-MHD (2), indomethacin conjugated 1-MHD (3), and naproxen conjugated 1-MHD (4).

Figure 3

(a) and (b) Binding model of 1-MHD with cyclooxygenases-1 (COX-1) and cyclooxygenases-2 (COX-2). (c) and (d) Binding model of 2 with COX-1 and COX-2.

Figure 4

X-ray single crystal analysis. Left: Chemical structure of 2. Middle: Top view of the X-ray single crystal structure. Right: Side view. Oak Ridge thermal ellipsoid plot program (ORTEP) for crystal structure represents 50% possibility.

Figure 5

The antitussive plots of number of coughs and the inhibition percentages of different agents.

Figure 6

(a) The efficacy of different agents at the same dosage 100 mg/Kg. (b) the inhibition of 2 at different dosage level. * p < 0.05, for comparison to treated groups with control.

Figure 7

Lung tissue histology analysis. (a) Representative hematoxylin and eosin-stained mouse lung sections with control group. (b) Mouse lung sections of PM 2.5 group. Arrows point out the thickened alveolar septum, dilated telangiectasia, and neutrophil. (c), (d), and (e) Mouse lung sections with treatment of 1-MHD, ASP, and 2, respectively. Note: Red arrow, neutrophil; yellow arrow, alveolar septum; green arrow, capillaries.