00857nas a2200145 4500008004100000245012100041210006900162260000800231300001600239490000700255520026700262100002600529700002800555856012800583 2015 eng d00aChiral pool approach for the synthesis of functionalized amino acids: synthesis of antiepileptic drug (R)-lacosamide0 aChiral pool approach for the synthesis of functionalized amino a cAUG a5802–58030 v563 a

An efficient total synthesis of (R)-lacosamide 1 has been achieved from N-Boc-N,O-isopropylidene-l-serinol 2 which could easily be obtained from natural l-serine. Our synthesis of 1 starting from 2 using chiral pool strategy resulted in 54% overall yield.

1 aAratikatla, Eswar, K.1 aBhattacharya, Asish, K. uhttps://library.ncl.res.in/content/chiral-pool-approach-synthesis-functionalized-amino-acids-synthesis-antiepileptic-drug-r03623nas a2200229 4500008004100000245018000041210006900221260000800290300001100298490000800309520275800317100002603075700001903101700002703120700001803147700001503165700002803180700002003208700001803228700002803246856011903274 2021 eng d00aCombating multi-drug resistant malaria parasite by inhibiting falcipain-2 and heme-polymerization: Artemisinin-peptidyl vinyl phosphonate hybrid molecules as new antimalarials0 aCombating multidrug resistant malaria parasite by inhibiting fal cAUG a1134540 v2203 a

Artemisinin-based combination therapies (ACTs) have been able to reduce the clinical and pathological malaria cases in endemic areas around the globe. However, recent reports have shown a progressive decline in malaria parasite clearance in South-east Asia after ACT treatment, thus envisaging a need for new artemisinin (ART) derivatives and combinations. To address the emergence of drug resistance to current antimalarials, here we report the synthesis of artemisinin-peptidyl vinyl phosphonate hybrid molecules that show superior efficacy than artemisinin alone against chloroquine-resistant as well as multidrug-resistant Plasmodium falciparum strains with EC50 in pico-molar ranges. Further, the compounds effectively inhibited the survival of ring-stage parasite for laboratory-adapted artemisinin-resistant parasite lines as compared to artemisinin. These hybrid molecules showed complete parasite clearance in vivo using P. berghei mouse malaria model in comparison to artemisinin alone. Studies on the mode of action of hybrid molecules suggested that these artemisinin-peptidyl vinyl phosphonate hybrid molecules possessed dual activities: inhibited falcipain-2 (FP-2) activity, a P. falciparum cysteine protease involved in hemoglobin degradation, and also blocked the hemozoin formation in the food-vacuole, a step earlier shown to be blocked by artemisinin. Since these hybrid molecules blocked multiple steps of a pathway and showed synergistic efficacies, we believe that these lead compounds can be developed as effective antimalarials to prevent the spread of resistance to current antimalarials.

1 aAratikatla, Eswar, K.1 aKalamuddin, Md1 aRana, Kalpeshkumar, C.1 aDatta, Gaurav1 aAsad, Mohd1 aSundararaman, Srividhya1 aMalhotra, Pawan1 aMohmmed, Asif1 aBhattacharya, Asish, K. uhttps://library.ncl.res.in/content/combating-multi-drug-resistant-malaria-parasite-inhibiting-falcipain-2-and-heme