Synthesis Of Bedaquiline Derivatives And The Evaluation Of Their Anti-tubercular Bacterial Activity

Bedaquiline(1)is a new drug for tuberculosis and the first of the diarylquinoline class.It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses,has a long terminal elimination half-life(due to its high lipophilicity),and exhibits potent hERG channel inhibition,resulting in clinical QTc interval prolongation.In view of the wide application of cyclopropyl in the design of drug molecules,we intend to introduce the 6-position of quinoline ring of Bedaquiline,the 4-position of naphthalene ring,and the 3-position and 4-position of phenyl ring-substituted naphthalene ring.A cyclopropyl group or a propyl group-containing ester,amide or the like is easily metabolized,and it is desirable to shorten the metabolic time while ensuring the efficacy.After a variety of synthetic methods,the target product was finally prepared by introducing a cyclopropyl group by a Negishi coupling reaction.Firstly,the aryl ketone derivative and the quinoline derivative are added at a low temperature,and the chiral separation is carried out to obtain a single-rotor(1R,2S)containing a key chiral intermediate of two chiral centers,and then with a ring.The propyl zinc reagent is separated by a Negishi coupling reaction through a chiral preparative column,and the target product containing a cyclopropyl group.A total of 28 new compounds(including intermediates)were synthesized,all of which were first reported new compounds.Their structures were confirmed by 1H-NMR,13C-NMR and HR-MS.The configuration of some compounds was X-ray single crystal.Diffraction confirmed.The bacteriostatic activity was tested for 24 of the compounds(target compounds and intermediates having basic frameworks and reaction by-products)to obtain 5 more active cyclopropyl-containing compounds.a compound in which a cyclopropyl group-containing Y2 group is introduced at the 6-position of a quinoline ring,the activity of which is 3-4 times that of the Bedaquiline,the cyclopropylcarboxylate introduced at the position,the trans configuration Ethyl cyclopropylcarboxylate is more active than cis,and is 20% of the activity of Bedaquiline.The ester group in the ethyl form of cyclopropylcarboxylate in trans configuration is converted to an amide,and the activity is greatly reduced.The cyclopropyl group and the cyclopropyl group-containing Y1 group are introduced at the 3-position after the benzene ring is substituted for the naphthalene ring,and the bacteriostatic activity is comparable to that of the Bedaquiline.In summary,the introduction of cyclopropyl compounds on the basis of the structure of Bedaquiline showed that some compounds had good inhibitory activity against Mycobacterium tuberculosis,and the 3-position of quinoline and phenyl ring substituted naphthalene ring had the best effect.After introducing Y1 into the 6-position of quinoline ring,compounds with stronger activity than Bedaquiline were obtained,but further optimization was needed.