Abstract
Malaria is a tropical threatening disease caused by Plasmodium parasites, resulting in 409,000 deaths in 2019. The delay of mortality and morbidity has been compounded by the widespread of drug resistant parasites from Southeast Asia since two decades. The emergence of artemisinin-resistant Plasmodium in Africa, where most cases are accounted, highlights the urgent need for new medicines. In this effort, the World Health Organization and Medicines for Malaria Venture joined to define clear goals for novel therapies and characterized the target candidate profile. This ongoing search for new treatments is based on imperative labor in medicinal chemistry which is summarized here with particular attention to hit-to-lead optimizations, key properties, and modes of action of these novel antimalarial drugs. This review, after presenting the current antimalarial chemotherapy, from quinine to the latest marketed drugs, focuses in particular on recent advances of the most promising antimalarial candidates in clinical and preclinical phases.
Keywords: Malaria, Plasmodium, clinical trials, drug development, drug discovery, medicines, mode of action.
[http://dx.doi.org/10.1056/NEJMc0805011] [PMID: 19064625]
[http://dx.doi.org/10.1038/nm.4381] [PMID: 28777791]
[http://dx.doi.org/10.1038/nrmicro.2017.161] [PMID: 29355852]
[http://dx.doi.org/10.1186/1475-2875-12-187] [PMID: 23742293]
[http://dx.doi.org/10.1186/s12936-016-1675-x] [PMID: 28086874]
[http://dx.doi.org/10.1007/s40265-018-0911-9] [PMID: 29802605]
[http://dx.doi.org/10.1016/j.coph.2018.05.006] [PMID: 29860174]
[http://dx.doi.org/10.1039/C7MD00637C] [PMID: 30108934]
[http://dx.doi.org/10.1186/s12936-019-2724-z] [PMID: 30902052]
[http://dx.doi.org/10.1016/S1473-3099(15)00246-7]
[http://dx.doi.org/10.1186/1475-2875-10-144] [PMID: 21609473]
[http://dx.doi.org/10.1017/mdh.2013.69] [PMID: 24331212]
[http://dx.doi.org/10.1126/science.1105787] [PMID: 1105787]
[http://dx.doi.org/10.2165/00003495-199345030-00009] [PMID: 7682911]
[http://dx.doi.org/10.1016/S0140-6736(82)91532-X] [PMID: 6128616]
[http://dx.doi.org/10.1016/S0140-6736(04)16767-6] [PMID: 15288742]
[http://dx.doi.org/10.1073/pnas.91.3.1143] [PMID: 8302844]
[http://dx.doi.org/10.1016/0166-6851(93)90252-S] [PMID: 8426608]
[http://dx.doi.org/10.1086/507115] [PMID: 16845638]
[http://dx.doi.org/10.1016/j.ijpara.2010.04.001] [PMID: 20399785]
[http://dx.doi.org/10.1038/nmicrobiol.2017.31] [PMID: 28288098]
[http://dx.doi.org/10.1007/s10495-016-1265-y] [PMID: 27357656]
[http://dx.doi.org/10.1021/acschembio.9b00003] [PMID: 30986346]
[http://dx.doi.org/10.1586/eri.09.68] [PMID: 19803708]
[http://dx.doi.org/10.1021/cb300454t] [PMID: 23043646]
[http://dx.doi.org/10.1086/427997] [PMID: 15717281]
[http://dx.doi.org/10.2174/156802606776743147] [PMID: 16719804]
[http://dx.doi.org/10.1016/S1473-3099(19)30543-2] [PMID: 31657776]
[http://dx.doi.org/10.1016/S1473-3099(16)30415-7] [PMID: 27818097]
[http://dx.doi.org/10.1172/JCI101980] [PMID: 16695643]
[http://dx.doi.org/10.2165/00003495-200565010-00004] [PMID: 15610051]
[http://dx.doi.org/10.1128/CMR.00011-19] [PMID: 31366609]
[http://dx.doi.org/10.1186/1475-2875-11-259] [PMID: 22856549]
[http://dx.doi.org/10.1186/1475-2875-12-212] [PMID: 23782898]
[http://dx.doi.org/10.1016/j.pharmthera.2016.03.011] [PMID: 27016470]
[http://dx.doi.org/10.1097/QCO.0000000000000574] [PMID: 31305490]
[http://dx.doi.org/10.1128/AAC.43.3.598] [PMID: 10049273]
[http://dx.doi.org/10.1186/1475-2875-13-2] [PMID: 24386891]
[http://dx.doi.org/10.1186/s12936-016-1145-5] [PMID: 26888075]
[http://dx.doi.org/10.1186/s12936-016-1632-8] [PMID: 27923405]
[http://dx.doi.org/10.1016/j.neurobiolaging.2010.12.012] [PMID: 21316815]
[http://dx.doi.org/10.1016/S0014-5793(98)00031-3] [PMID: 9498806]
[http://dx.doi.org/10.1186/s12916-018-1045-3] [PMID: 29690878]
[http://dx.doi.org/10.1371/journal.pone.0222993] [PMID: 31600221]
[http://dx.doi.org/10.1016/0035-9203(92)90414-8] [PMID: 1566313]
[http://dx.doi.org/10.1186/1475-2875-11-270] [PMID: 22877082]
[http://dx.doi.org/10.1002/bip.23398] [PMID: 33280083]
[http://dx.doi.org/10.1128/AAC.00394-06] [PMID: 16940111]
[http://dx.doi.org/10.1016/j.molbiopara.2007.01.005] [PMID: 17289168]
[http://dx.doi.org/10.1186/s12936-016-1114-z] [PMID: 26873741]
[http://dx.doi.org/10.1016/0006-2952(92)90213-3] [PMID: 1314606]
[http://dx.doi.org/10.1006/expr.1995.1049] [PMID: 7729473]
[http://dx.doi.org/10.1111/j.1476-5381.1953.tb00758.x] [PMID: 13066702]
[PMID: 23573546]
[http://dx.doi.org/10.1128/AAC.43.6.1334] [PMID: 10348748]
[http://dx.doi.org/10.1093/jac/dkl104] [PMID: 16617066]
[http://dx.doi.org/10.1016/j.pt.2016.05.010] [PMID: 27289273]
[http://dx.doi.org/10.1038/ncomms10111] [PMID: 26694030]
[http://dx.doi.org/10.1016/S1875-5364(19)30038-X] [PMID: 31171267]
[http://dx.doi.org/10.1038/nature01813] [PMID: 12931192]
[http://dx.doi.org/10.1038/nature14412] [PMID: 25874676]
[http://dx.doi.org/10.3109/10408441003610571] [PMID: 20158370]
[http://dx.doi.org/10.1016/j.pt.2019.05.002] [PMID: 31176584]
[http://dx.doi.org/10.1038/nature02779] [PMID: 15318224]
[http://dx.doi.org/10.1021/jm049040u] [PMID: 16033274]
[http://dx.doi.org/10.1128/AAC.00225-07] [PMID: 17562801]
[http://dx.doi.org/10.1021/jm901473s] [PMID: 19924861]
[http://dx.doi.org/10.1086/655831] [PMID: 20687837]
[http://dx.doi.org/10.4103/2141-9248.139270] [PMID: 25221689]
[http://dx.doi.org/10.1128/AAC.01064-06] [PMID: 17145800]
[http://dx.doi.org/10.1021/acsinfecdis.9b00257] [PMID: 31622078]
[http://dx.doi.org/10.1007/s40265-016-0572-5] [PMID: 27075024]
[http://dx.doi.org/10.1016/B978-0-12-813133-6.00008-1]
[http://dx.doi.org/10.1186/s12936-015-0919-5] [PMID: 26445424]
[http://dx.doi.org/10.3390/ph3123581]
[http://dx.doi.org/10.1073/pnas.1015762108] [PMID: 21300861]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01586] [PMID: 28052200]
[http://dx.doi.org/10.1111/j.1365-2125.2012.04368.x] [PMID: 22759078]
[http://dx.doi.org/10.1016/S1473-3099(15)00320-5] [PMID: 26448141]
[http://dx.doi.org/10.1093/jac/dkw174] [PMID: 27272721]
[http://dx.doi.org/10.1128/AAC.01371-19] [PMID: 31685476]
[http://dx.doi.org/10.1186/s12916-017-0940-3] [PMID: 28988541]
[http://dx.doi.org/10.4269/ajtmh.1996.55.579] [PMID: 9025680]
[http://dx.doi.org/10.1021/jm980146x] [PMID: 9836608]
[http://dx.doi.org/10.1371/journal.pctr.0020006] [PMID: 17213921]
[http://dx.doi.org/10.1080/10915810490471352] [PMID: 15204721]
[http://dx.doi.org/10.1016/S1473-3099(17)30365-1] [PMID: 28916443]
[http://dx.doi.org/10.1021/jm970401y] [PMID: 9371235]
[http://dx.doi.org/10.1007/s004360000317] [PMID: 11293573]
[http://dx.doi.org/10.1124/dmd.104.003202] [PMID: 16415117]
[http://dx.doi.org/10.1016/S0968-0896(99)00224-2] [PMID: 10658588]
[http://dx.doi.org/10.1128/AAC.05359-11] [PMID: 22430976]
[http://dx.doi.org/10.1093/jac/dkz340] [PMID: 31518407]
[http://dx.doi.org/10.1186/1475-2875-5-11] [PMID: 16464254]
[http://dx.doi.org/10.1186/1475-2875-10-53] [PMID: 21362162]
[http://dx.doi.org/10.1186/s12936-016-1511-3] [PMID: 27624471]
[http://dx.doi.org/10.1016/S1473-3099(15)00079-1] [PMID: 26342427]
[http://dx.doi.org/10.1021/mp800007x] [PMID: 18563912]
[http://dx.doi.org/10.1073/pnas.0802982105] [PMID: 18579783]
[http://dx.doi.org/10.1021/jm2003359] [PMID: 21644570]
[http://dx.doi.org/10.1021/jm300041e] [PMID: 22524250]
[http://dx.doi.org/10.1128/AAC.02727-13] [PMID: 24913172]
[http://dx.doi.org/10.1128/AAC.03478-14] [PMID: 25136017]
[http://dx.doi.org/10.1186/s12936-017-2162-8] [PMID: 29304859]
[http://dx.doi.org/10.1056/NEJMoa1602250] [PMID: 27653565]
[http://dx.doi.org/10.1038/nmicrobiol.2016.166] [PMID: 27642791]
[http://dx.doi.org/10.1038/s41467-020-15440-4] [PMID: 32286267]
[http://dx.doi.org/10.1126/science.1193225] [PMID: 20813948]
[http://dx.doi.org/10.1021/jm100410f] [PMID: 20568778]
[http://dx.doi.org/10.1128/AAC.06377-11] [PMID: 22508309]
[http://dx.doi.org/10.1128/AAC.03393-14] [PMID: 25114127]
[http://dx.doi.org/10.1124/dmd.115.069187] [PMID: 26921387]
[http://dx.doi.org/10.1128/AAC.01423-20] [PMID: 33199389]
[http://dx.doi.org/10.1128/AAC.00340-15] [PMID: 25845867]
[http://dx.doi.org/10.1056/NEJMoa1315860] [PMID: 25075833]
[http://dx.doi.org/10.1128/AAC.01940-16] [PMID: 27872070]
[http://dx.doi.org/10.1016/j.chom.2012.12.006] [PMID: 23414762]
[http://dx.doi.org/10.1038/nature09099] [PMID: 20485428]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00752] [PMID: 27505686]
[http://dx.doi.org/10.1073/pnas.1414221111] [PMID: 25453091]
[http://dx.doi.org/10.1016/S1473-3099(19)30611-5] [PMID: 32275867]
[http://dx.doi.org/10.1038/nature09107] [PMID: 20485427]
[http://dx.doi.org/10.1021/jm3001373] [PMID: 22390538]
[http://dx.doi.org/10.1126/scitranslmed.aad9735] [PMID: 28446690]
[http://dx.doi.org/10.1093/cid/ciaa368] [PMID: 32239164]
[http://dx.doi.org/10.1128/AAC.01896-19] [PMID: 31932368]
[http://dx.doi.org/10.1038/nature12782] [PMID: 24284631]
[http://dx.doi.org/10.2174/187152610791163336] [PMID: 20334617]
[http://dx.doi.org/10.1021/jm8001026] [PMID: 18522386]
[http://dx.doi.org/10.1021/jm200592f] [PMID: 21696174]
[http://dx.doi.org/10.1126/scitranslmed.aaa6645] [PMID: 26180101]
[http://dx.doi.org/10.1016/S1473-3099(17)30171-8] [PMID: 28363636]
[http://dx.doi.org/10.1016/S1473-3099(18)30309-8] [PMID: 29909069]
[http://dx.doi.org/10.1016/S1473-3099(17)30139-1] [PMID: 28363637]
[http://dx.doi.org/10.1093/infdis/jix613] [PMID: 29216395]
[http://dx.doi.org/10.1002/anie.200503071] [PMID: 16444785]
[http://dx.doi.org/10.1093/jac/dkl563] [PMID: 17337512]
[http://dx.doi.org/10.1186/1475-2875-9-227] [PMID: 20691118]
[http://dx.doi.org/10.3389/fphar.2020.00846] [PMID: 32595499]
[http://dx.doi.org/10.1128/AAC.02106-20] [PMID: 33558284]
[http://dx.doi.org/10.1128/AAC.01585-07] [PMID: 18559649]
[http://dx.doi.org/10.1371/journal.pone.0172718] [PMID: 28249043]
[http://dx.doi.org/10.1371/journal.pone.0188754] [PMID: 29244851]
[http://dx.doi.org/10.1086/598222] [PMID: 19392627]
[http://dx.doi.org/10.1086/605431] [PMID: 19673614]
[http://dx.doi.org/10.1371/journal.ppat.1003980] [PMID: 24603727]
[http://dx.doi.org/10.1186/s12936-017-1858-0] [PMID: 28535809]
[http://dx.doi.org/10.1126/science.285.5433.1573] [PMID: 10477522]
[http://dx.doi.org/10.2217/FMB.15.60] [PMID: 26228767]
[http://dx.doi.org/10.4269/ajtmh.16-0332] [PMID: 27215296]
[http://dx.doi.org/10.1002/14651858.CD006688.pub2] [PMID: 21328286]
[http://dx.doi.org/10.1016/j.bcmd.2015.05.007] [PMID: 26142327]
[http://dx.doi.org/10.1371/journal.pone.0164895] [PMID: 27768734]
[http://dx.doi.org/10.1038/ncomms7715] [PMID: 25823686]
[http://dx.doi.org/10.1002/cmdc.201600298] [PMID: 27471138]
[http://dx.doi.org/10.1128/AAC.04125-14] [PMID: 25421475]
[http://dx.doi.org/10.1371/journal.pmed.1002138] [PMID: 27701420]
[http://dx.doi.org/10.1111/mmi.13397] [PMID: 27073104]
[http://dx.doi.org/10.1111/bcp.12962] [PMID: 27062080]
[http://dx.doi.org/10.3389/fcimb.2018.00256] [PMID: 30094226]
[http://dx.doi.org/10.1038/nature14451] [PMID: 26085270]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00723] [PMID: 27631715]
[http://dx.doi.org/10.1128/AAC.02181-19] [PMID: 32041711]
[http://dx.doi.org/10.1073/pnas.1204556109] [PMID: 23035243]
[http://dx.doi.org/10.1038/nsb921] [PMID: 12704428]
[http://dx.doi.org/10.1016/j.ijpara.2020.12.002] [PMID: 33713651]
[http://dx.doi.org/10.1111/bcp.14219] [PMID: 31925817]
[http://dx.doi.org/10.4269/ajtmh.20-1165] [PMID: 33556040]
[http://dx.doi.org/10.1128/AAC.00645-07] [PMID: 18378716]
[http://dx.doi.org/10.1021/jm00351a017] [PMID: 7131488]
[http://dx.doi.org/10.1371/journal.pmed.1001169] [PMID: 22363211]
[http://dx.doi.org/10.3389/fphar.2019.01265] [PMID: 31708786]
[http://dx.doi.org/10.1128/AAC.03762-14] [PMID: 25331702]
[http://dx.doi.org/10.1128/AAC.05326-11] [PMID: 22314528]
[http://dx.doi.org/10.1128/AAC.03066-15] [PMID: 26856849]
[http://dx.doi.org/10.1128/AAC.01335-17] [PMID: 29311093]
[http://dx.doi.org/10.1128/AAC.01538-19] [PMID: 31843994]
[http://dx.doi.org/10.1074/mcp.RA119.001797] [PMID: 31836637]
[http://dx.doi.org/10.1128/AAC.34.7.1381] [PMID: 2201254]
[http://dx.doi.org/10.1128/AAC.45.9.2577-2584.2001] [PMID: 11502532]
[http://dx.doi.org/10.1016/j.bmcl.2004.01.083] [PMID: 15050641]
[http://dx.doi.org/10.1038/ncomms14193] [PMID: 28139658]
[http://dx.doi.org/10.1186/s12936-018-2279-4] [PMID: 29558913]
[http://dx.doi.org/10.1126/scitranslmed.3005029] [PMID: 23515079]
[http://dx.doi.org/10.1021/jm500147k] [PMID: 24720377]
[http://dx.doi.org/10.1128/AAC.01183-15] [PMID: 26124159]
[http://dx.doi.org/10.1021/acsinfecdis.7b00062] [PMID: 28927276]
[http://dx.doi.org/10.1080/10837450.2020.1725893] [PMID: 32031478]
[http://dx.doi.org/10.1186/s12936-019-2921-9] [PMID: 31455339]
[http://dx.doi.org/10.1128/AAC.00791-16] [PMID: 27270285]
[http://dx.doi.org/10.1038/ncomms15159] [PMID: 28537265]
[http://dx.doi.org/10.1002/anie.201001026] [PMID: 20629058]
[http://dx.doi.org/10.1038/nature19804] [PMID: 27602946]
[http://dx.doi.org/10.1371/journal.pone.0054974] [PMID: 23405100]
[http://dx.doi.org/10.1128/AAC.04970-14] [PMID: 25845876]
[http://dx.doi.org/10.1126/scitranslmed.aas9917] [PMID: 31534021]
[http://dx.doi.org/10.1021/acsinfecdis.6b00144] [PMID: 27641613]
[http://dx.doi.org/10.1016/j.exppara.2006.03.014] [PMID: 16828746]
[http://dx.doi.org/10.1038/nature07937] [PMID: 19357645]
[http://dx.doi.org/10.1021/acs.jmedchem.8b01961] [PMID: 30852885]
[http://dx.doi.org/10.1021/acs.jmedchem.0c00539] [PMID: 32390431]
[http://dx.doi.org/10.1021/acsptsci.0c00078] [PMID: 33073193]
[http://dx.doi.org/10.1073/pnas.1306097110] [PMID: 23836641]
[http://dx.doi.org/10.1038/s41421-020-00215-4] [PMID: 33311461]
[http://dx.doi.org/10.1016/j.cclet.2020.12.023]