| Structural modification research based on natural products is an important way for drug research and development.Protoberberine alkaloids,a class of isoquinoline alkaloids,have various pharmacological activities and the representative compounds include berberine,palmatine(Figure 1).Based on the protoberberine skeleton,various chemical modification strategies have been used in this research to obtain active compounds against Acinetobacter baumannii(A.baumannii)and hepatic fibrosis with high efficiency and low toxicity.A.baumannii has provided a major and global threat to health care system,thus it is urgent to find novel antibacterial strategies.Nowadays,the auxiliary antibacterial strategy combined with traditional antibiotics to improve their antibacterial activity has become a research hotspot.Our group found that berberine shows moderate synergistic anti-A.baumannii which deserves further structural optimization.In the first part,thirty-four novel berberine derivatives were synthesized and the antibacterial structureactivity relationship(SAR)of BBR derivatives were summarized that the open of methylene-dioxy ring was not beneficial for activity and the 9-position derivatives showed better synergistic antibacterial activity.Also,C ring conjugated structures were essential fragments for activity.Among them,the fractional inhibitory concentration index(FICI)of representative compound 2d combined with aztreonam was 0.129.2d could significantly increase the potency of aztreonam against A.baumannii,including carbapenem-resistant and extended-spectrum β-lactamases-producing strains.Moreover,synergistic effects were observed when combining 2d with different classes of antibiotics used in clinical practices.2d could markedly improve the survival rates of Galleria mellonella larvae when combined with aztreonam,compared with aztreonam treatment alone.Mechanism studies indicated that 2d may inhibit the drug efflux and iron acquisition of the bacteria through targeting the AdeB transporter protein,thus achieving a synergistic antimicrobial efficacy with different antibacterials.Therefore,berberine derivatives represent a new family of antimicrobial adjuvants against A.baumannii.The intervening of hepatic fibrosis has been recognized as the promising strategy to delay NASH progress.Abnormal over-expression of COL1(collagen type Ⅰ)is the basic feature of liver fibrosis.Our group firstly found that 9-p-isopropyl-palmatine bromide(P1)was able to down-regulate COL1A1-promotor activity(Figure 2).However,it failed to show good in vivo anti-hepatic fibrogenesis activity.Therefore,twenty-eight palmaltine derivatives were designed and synthesized taking P1 as the lead compound in the second part.And a total of sixty-two derivatives were evaluated for their inhibitory effect against COL 1A1-promotor.The overall SAR indicated that 9-position ether benzyl substitution displays good activities against COL 1A1-promotor and the introduction of an appropriate 13-substitution may lead to the retain of activity.Among them,representative compound z1 showed similar in vitro anti-COL1A1promotor activity as the lead compound,with an inhibition rate of 72.4%.The oral LD50 value of z1 in mice was>1000 mg/kg,with good in vivo safety.In addition,z1 showed good anti-hepatic fibrosis activity in vivo in choline-deficient,L-amino acid-defined,high-fat diet(CDAHFD)mice model andbile duct ligation(BDL)rat model.Mechanism study indicated that it may significantly ameliorated hepatic fibrogenesis by activating farnesoid X receptor(FXR).Therefore,palmatine derivatives constituted a new family of anti-hepatic fibrosis candidates.In this study,sixty-two novel berberine derivatives were synthesized.This research has provided two active compounds with high efficiency and low toxicity for the treatment strategy of A.baumannii and liver fibrosis,enriching the structural types and pharmaceutical applications of protoberberine compounds. |
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