Malaria Treatment Drugs: Resistance And Exploration

Discuss about the S215 Chemistry: Essential Concepts. To my course mates I remain thankful to you too for the creation of the conducive environment for the studies and above all to my lecturers who have been so resourceful in this task.

The Complex Life Cycle of the Plasmodium Parasite

There were individuals who really helped me in the various stages of my project. My sincere appreciation goes to the technician who made the reagents available for my experiments. To my course mates I remain thankful to you too for the creation of the conducive environment for the studies and above all to my lecturers who have been so resourceful in this task

Several efforts have been put in place to help in the controlling of the malaria and even possibly have it completely eradicated. Although there has been success in some other parts of the world including Southern Europe among other countries in the Africa and in the Middle East, other regions in the world still experience the fatal effects of this particular disease. The reasons as to why this has been the case is because of the continued resistance of the parasites of malaria to the drugs available (Koesdjojo et.al 2014).

The complex life cycle of this plasmodium is another reason for the spreading of this disease. Malaria especially for the human is initiated by infection caused by the plasmodium parasite. This is transmitted to human host through an infected female mosquito called Anopheles. After getting into the host, its circulation begins with the phase of sexual life cycle in which the parasite quickly moves to the liver. This stage is very silent and it is merely described as the liver infection. The stage is characterised by the formation of thousands of merozoites that are subsequently released into the bloodstream.

Once in the bloodstream, they invade the red blood cells and this becomes the beginning of the pathogenic asexual life cycle. In very many countries, the manufacturing operations have been made easier using lean manufacturing. This task however appears to be very much challenging. There are very many factors that influence this method of manufacturing of these factors are complex in their properties and are therefore much challenging. The rules that have been put in place can actually help in the reduction of the time that is consumed in the process of production.

This is only possible when these principles are applied accordingly. The purpose of this project is to shed much light on the manner of the application of these principles and their resultant effects which may be termed as positive or disadvantages in some cases. The required steps of the smooth operation are basically laid down in a very systematic framework. This opera ration frame work also explains the depth of the applications that either directly or indirectly reduces the throughput time.

Resistance of Malaria Treatment Drugs

 The resistance of the malaria parasites to the past versions of the medicines has seriously undermined the malaria control efforts. During the previous decades, therapies that are based on the combination of the artemisinin have been developed in the world as the first attempts of malaria treatment. This has been commonly referred to as ACTs. ACTs include a fast-acting artemisinin compound and another drug that is meant to improve the efficacy so as to hinder the emergence of the resistance to artemisinin. Increase in the quantity of the compound especially in the terms of its bulkiness in the branch R which actually seems to improve the activity of the vitro.

As had been indicated in the past results, the IC50 values for the series 7 demonstrated a perfect correlation with all the clog pf P and the parameters of the Charton. Other new series including series 9 also gave a fair correlation with these very parameters of ACharton but there was an exception to the values of the clog P. The supporting data as indicated in the series 10 was actually too small to permit the drawing of the convincing conclusion on the same subject. The HEFLECINs having the chloroquinoline core was actually found to be more active as opposed to that of the CQ. The two compounds that are also known as 7C and 7h had their activities meeting the requirement of the selected studies. Lean manufacturing of drugs helps in the reduction of the crucial step. The processing time is reduced, cost of the operation minimised and quality of the services and products improved with the application of this drug manufacturing tool. The errors that are predictable can be foreseen and corrected in advance using what is called preventive maintenance.

The reliability of the suppliers to the companies doing manufacturing will for sure improve without any doubt. The initiative has led to the increased profitability within the companies and even the improved public impression and perception. Among the companies that have benefited for this initiative include those that are dealing with the perishable goods whose delivery must be done within the specific duration of the time. The provision of emergency responses like for the medical services have been realised the generation of descriptive terminologies, lean manufacturing has been known to be the lean production. In the production set up, these initiative plays avital role in the production line where it lowers the production cost using relevant tools within the shortest time possible.

Lean Manufacturing of Drugs and Reduction of Processing Time

However, there is now even a bigger challenge considering that there are signs indicating malaria parasite resistance to this artemisinin. Of concern now is the dependence on the new drug combination on the derivatives of the artemisinin. It is worrying that most of the antimalarial drugs that are available only target the blood-stage parasites with very few known to inhibit the activities of the liver stage parasites (Lelièvre et.al 2012).

 In the clinical drugs used worldwide, only Primaquine acts against the operations of the parasites at the liver stage. Due to the concerns of the continued resistance to the antimalarial drugs along the effects of difficult-to-treat chronic liver stages, the recommended therapy should be effective enough to act against the multi-resistant strains of the parasite and also to be active against the two stages of the parasites both for the liver and for the erythrocytes.

The aim of this project is study the existing drugs of the antimalaria and possibly make improvements on the ones that are already facing resistance from the plasmodium species.

The approach that was used in this particular project which was the heme-targeted antimalarial employed the utilisation of very cheap materials. The step that was used however was very much high yielding. There was amination of 4,7-dichloroquinoline with the compound called diaminoalkanes whose concentration was kept between 82-90% yield. Combination of this compound with N, N diethylamino-3-propionic acid together alongside another compound called 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide was done. The furnished amides were then lowered using borane to the corresponding series of secondary amines. This was then followed by the preparation of the tertiary amines by doing the treatment of the precursor using another compound called sodium borohydride but within a special type of acetic solution. (Peters 2013).

The extended amines marked 6 and 7 could be made using an acid called 4-ketopimelic,8 and 5-oxoacelaic acid marked 9. The obtained results indicated that CDMT and Pybop when thoroughly combined allows for the efficient formation with other compounds such as diethylamine and even with diisopropylamine as followed. The corresponding yield of the diamides that were marked 10 and 11 were between 62-99%. The triamines yields marked 14 and 15 were as a result of the group of ketones that have lowered amination from acetate of ammonia and cyanoborohydride of sodium (Jover et.al 2012) 

The terminal amides were reduced using another important compound called lithium aluminium hydride. There was very careful but optimised nucleophilic aromatic constitution used to employ these amines at high temperatures and in the presence of 1. This was done in a closed vessel and it resulted into the production of chloroquinolines that were marked 6 and 7 respectively. A mixture of these elements of the isomers together with trans-isomers of diaminocyclohexane which were temporarily marked 18 and 19 together with4,7-dichlorpoquinoline were used to prepare 1,3-and 1,4-diaminocylohexane. This was obtained from chloroquinolines that were marked 16a,16b,17a and finally 17b in that order. This process was then followed by the intermediate treatment of 20 and 21 using acetic acid and NaBH4.

Current Efforts to Combat Malaria

The activity of the tribasic compound marked 4a-e,5 a-e,7a, b and 6a, b was considered ant plasmodial. These properties were also shown by the compounds of the dibasic 1,3-and 1,4-diaminocyclohexane in the tubes marked 18 and 19. This was measured against other two CRQs which included HB3 and GCO3 and also Dd2 and FCB elements with the standardised and found in many laboratories. The calculations of the values of IC50 was done from the experiment that was performed in triplicate then compared to the values of the CQ as shown in the table labelled 1.

Most of the aminoquinolines that were prepared during the project indicated antimalarial activity against the HB3 and the GCO3.This was the same as the case of the CQ. A good number of the compounds that were found significantly demonstrated to be potent against the strains of the resistant in Dd2 and FCB as opposed to the compound CQ. Among the compounds that were treated which were 18, only 49% gave the values of IC50 between 28 to 81 nM. In the case of Dd2, CQIC50 was equivalent to 140nM and out of 8, l6 indicated values of IC50 between 49.1 and 74nM for the FCB which is the CQIC50.

It was however discovered that the activity of the antimalarial of those linear tribasic aminoquinolines marked 4a up to e and also 5a up to e were generally superior over other compounds in the tubes marked 6a,7a,6b and finally 7b leading to a systematically side chain that was branched (Delves et.al 2013). The same antimalarial activity was observed with the highly branched analogues 16a,17a,16b and 17b which were the branched dibasic of CQ. These compounds however were characterised by very high index of selectivity. It is important to note that diastereomeric mixtures of these compound marked 17a and 16a had been previously been prepared by Drake.

Their report indicated higher antimalarial activity against the compounds such as CQS and CQR elements as opposed to the compound of chloroquine. The quantitative measure was therefore provided by this selectivity index and this probably indicated the discovery leads of the drug. The selectivity index of CQ was at 10 while all other compounds that were tested gave values between a range of 0.68 and 4.43. This implied that there was need to have 5a and 5b highly combined so as to produce an antimalarial activity that is required against HB3 and GCO3 but this should be vacillated wiry the very low values of the selectivity index. The recommended range should be between 1.14 and 1.78.

The present hem targeted antiplasmodial therefore show activity against CQS strains that were the same as those of CQ. They however retained their potency against the strains of CQR.When the antimalarial activities of 5a and 5b were compared with the results that were gotten from the tribasic aminoquinolines 4a and 4b indicates that the presence of this amino acid is very important for the activity of Dd2, FCB andGCO3.The other compound such as HB3 was however not affected by this. Also, the effectiveness of 5a and 5b compared with Dd2 among others diminishes or reduces significantly with increase in the chai length. The values of the selective index of all the compounds tested illustrate that the differences witnessed on the CQ chain structure and even the basicity creates the new venues of overcoming the resistance to the antimalarial drugs.

This can be possibly being combined with another third compound of basic amino that will in turn favour the pilling of the drug inside the cell vacuole of the plasmodium parasite that is also acidic. The high IC50 that was observed within the compounds of 7a and finally 7b indicates the structure of the basicity of these chains especially branched ones that cannot be independently optimised.

For the entire period of this project, a lot of effort has been put on the design, evaluation and the possible synthesis of the promising antimalarial drugs while putting into the consideration of the properties of the synesthetic pathways that includes cheapness and being straight forward. The result given just indicates how the simple chemistry can actually yields the required antimalarial leads (Nayyar et.al 2013).

The compound that was registered as 8d was actually obtained by a single coupling of the compound called amide. This process was done done stepwise between the parent drug commonly known as PQ together with the required cinnamic acid. This was previously indicated by the standard condition of the coupling. This was done using the activation of the acid of the cinnamic with O, TBTU and in the presence of the compound called DIEA alongside the addition of PQ. The synthesis of the compound 14 was only the one that required the registered three steps. The three steps included coupling of the final results of the compound to the recommended acid of cinnamic which is also activated by the DIEA. During this synthesis, morpholine was reacted with the 1 N-phthaloyl which is actually 4-bromobutane and the followed by hydrazinolysis of the very compound. Although not all the compounds result into the yields that were relative above the average results.

The discovery of the potent in the use of the vitro operations of the CQ analogues marked 7 as compared against blood-stage CQ of the resistance to the plasmodium falciparum parasite was the major achievement’s is now an expansion in the family of the heterocycle. For some of the compounds, there was comparison of the activity of the 3D7 which is considered chlorine sensitive and the W2 Plasmodium falciparum parasite itself.

In addition to this, there was consideration in the structural analogy to CQ which actually operates through the inhibition of the element of the hematin. The selected compounds were evaluated as in the case of the vitro inhibitors. However, on the basis of the latest results that involved the use of the primaquine-cinnamic conjugate of the acid, there was an improved assessment in the vitro activity which is the subset of the HEFLECINs (Delves et.al 2012)

The blood-stage operations of this compound, HEFLECINs were actually determined by the methods and the procedures that have already been indicated before. The analysis of the data obtained indicated a summary of the most tests. Most of the compounds that were under the tests actually assayed against both the strains and these were very much active as compared to the CQ-resistant which was the W2 and also the CQ-sensitive(3D7) strain. The compounds that were obtained the samples 7,9 and even 10 but with that single branch that is attached to the group of cinnamoyl. The removal of the 7-chlorine branch from the chloroquinoline ring that connects to reduced activity of the antimalarial with the order of about 1. Finally, there was replacement of the bond of the amide in 7d whose IC50 is equivalent to 20nM to the 6; fold decrease activity of 122nM.

The substitution of the ring of the chloroquinoline that includes 7d which is equivalent to 20nM by possibly another ring of the heteroaromatic that could be 8-amino-6-methoxyquinoline and even pyridinic and this results to the reduced loss of the operations or the activity. The comparison of the index value of IC50 that has a series of either 7 or 9 and this actually translated into the substituent cinnamoyl R that has direct impact on the activity although this may not be dramatic. The property of the donation or the withdrawing character of R appears to be very insignificant in the activity itself. In most of these cases, the para position is normally liked over other positions including the Meta position and the Meta positions.

Increase in the quantity of the compound especially in the terms of its bulkiness in the branch R which actually seems to improve the activity of the vitro. As had been indicated in the past results, the IC50 values for the series 7 demonstrated a perfect correlation with all the clog pf P and the parameters of the Charton. Other new series including series 9 also gave a fair correlation with these very parameters of ACharton but there was an exception to the values of the clog P. The supporting data as indicated in the series 10 was actually too small to permit the drawing of the convincing conclusion on the same subject. The HEFLECINs having the chloroquinoline core was actually found to be more active as opposed to that of the CQ. The two compounds that are also known as 7C and 7h had their activities meeting the requirement of the selected studies (Movellan et.al 2014)

In the Vitro operation against B-Hematin formation was actually used to determine the ability of the HEFLECINs in the inhibition of the B-hematin to another compound called hemozoin. The properties that are related to the CQ and those connected to the antimalarial were assessed in the past results of the report of the method. This activity was not matching with the Vitro antimalarial operations that had been indicated thereby suggesting that HEFLECCINs owes this to the mechanisms set in place.

 In addition to this, inhibition of this haematin significantly contributes to the formation activity. It has facilitate a strong believe that b-hematin formation is being inhibited by the activities that are contributed due to the b-hematin variation  inhibition potency in the homologues like in the 7c, 10a, and 9b, that moves in the same trend  as compared to the variation  functions against the parasite of the  blood-stage and the decrease  of the significant within the antimalarial actions  in the consideration with the removal of the 7- chlorine  substituent (7c vs  12) with can be explained by the previous observation the chlorine atom used was essential in ensuring the effectiveness of b-hematin inhibition by CQ plus the related  structure.

Both the initial and the current finding can be winded up that HEFLECINs was unreactive against the blood stage parasite s via cysteine protease falcipians inhibition the function can be the new permeation pathway (NNPs) impairment that are manufactured by plasmodia inside the red blood cell (RBC) l with infection and b hematin crystallization inhibition. In the Vivo Treatment of P. berghei infected mice (Bruxvoort et.al 2014) for the most promising HEFLECINs, the compounds that were chosen has the potency against the cultured blood-stage.

 The mice were injected with the chemical substance called intraperitoneally(ip) with the p. berghei and then treated twice on everyday with other ip injections including 10 up to 100mg/The positive control used was chloroquine at the quantity of 3,10 and finally 30 mg/kg ip for two times within the year. The entire specimen which the mice were died due to the effects of the malaria. This death could be partially being attributed to the poisoning due to the drugs that were administered in the day 7.

Comparison of the time for survival especially after the start of the treatment was done so as to check on the compound efficacies. In the enclosed observation of the collected data, the compounds in the tube labelled 7C and also 7h were found to be very toxic at the concentration of the 100mg/kg. In the particular contrition, there were no mice that survived in the entire treatment process. At the lower doses of the treatment, 7h had an extension of the survival to the untreated control by 2-7 days at 30mg/kg and also by duration of the two days at 10mg/kg. It is very important to note that the sample 76C did not make any improvement on the samples as compared to the other untreated controls present in the setup (An et.al 2015)

 There was an extension of the survival to at least two days in comparison to the untreated controls at the largest amount of the dosage although this did not bring any advantage along with it.

In the broad summary, there had been preparation of a series of rather very new hemetargerted antimalarial that was actually achieved by getting the variation of the structure and the basicity of the side that was actually attached to the component of the CQ. The 18 components that were all tested indicated the potent of the antimalarial activity as opposed to those other 4 different kinds of strains in the vitro that can be synthesised from the readily available but cheap materials.

In particular, the tribasic 4-aminoquinolines 5a and its partner 5b possessing that short linear side chain together with the excess aliphatic amino acids were found to be very much effective for both CQS and CQR. This study has also shown the variations in the methodological variation of the similar side chains of the compound-chloroquine that ensures proper entry toward the affordable heme-targeted antimalarials that will finally assist in the overcoming of the increasingly resistance to the malarial drugs.

They however retained their impacts on the remains of CQR.When some antimalarial activities of 5b and 5a were compared against the data that were gotten from the alkaline aminoquinolines 4b and 4a indicates that the existence of this group acid is very important for the activity of Dd2, FCB andGCO3.The other compound such as HB3 was however not affected by this. Also, the effectiveness of 5a and 5b compared with Dd2 among others diminishes or reduces significantly with increase in the chai length. The values of the selective index of all the compounds tested illustrate that the differences witnessed on the CQ chain structure and even the basicity creates the new venues of overcoming the resistance to the antimalarial drugs.

Conclusion

A new family of the analogues of the chloroquine that is commonly known as HEFLECINs as the dual stage antimalaria leads was finally obtained. This particular compound shows a great potent in vitro activity that is required against both the liver and the blood stage plasmodia. This included the resistance that is also experienced in the chloroquine but in the stage of blood for the species of the plasmodium falciparum W2 parasites being the vector in this case.

The performance that was recorded was much better than the original chloroquine itself. The most effective combination was that of 7C and 7h. Also, all 11,14 and 13 were found to be better than that primaquine that is found to be somehow effective on the liver parasites. This clearly indicates that the compound 4-amino -7 -chloroquinolines motif plays very crucial duty in the activity of the dual stage of the antimalarial. In the process of the study, two of the compounds were actually found to be very much active especially against the model of malaria called murine/. The modest performances were in the vivo as opposed to the ones for vitro. This could be attributed to the bioavailability of the related issues that may require future optimisation of the antimalarial drugs.

References

An, J., Woodward, J.J., Sasaki, T., Minie, M. and Elkon, K.B., 2015. Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction. The Journal of Immunology, p.1402793.

Bruxvoort, K., Goodman, C., Kachur, S.P. and Schellenberg, D., 2014. How patients take malaria treatment: a systematic review of the literature on adherence to antimalarial drugs. PloS one, 9(1), p. e84555.

Delves, M., Plouffe, D., Scheurer, C., Meister, S., Wittlin, S., Winzeler, E.A., Sinden, R.E. and Leroy, D., 2012. The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites. PLoS medicine, 9(2), p. e1001169.

Delves, M.J., Recker, A., Straschil, U., Lelièvre, J., Marques, S., López-Barragán, M.J., Herreros, E. and Sinden, R.E., 2013. Male and female P. falciparum mature gametocytes show different responses to antimalarial drugs. Antimicrobial agents and chemotherapy, pp.AAC-00325.

Koesdjojo, M.T., Wu, Y., Boonloed, A., Dunfield, E.M. and Remcho, V.T., 2014. Low-cost, high-speed identification of counterfeit antimalarial drugs on paper. Talanta, 130, pp.122-127.

Lelièvre, J., Almela, M.J., Lozano, S., Miguel, C., Franco, V., Leroy, D. and Herreros, E., 2012. Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence “transmission blocking” assay. Malaria journal, 11(1), p. P7.

Nayyar, G.M., Breman, J.G., Newton, P.N. and Herrington, J., 2012. Poor-quality antimalarial drugs in Southeast Asia and sub-Saharan Africa. The Lancet infectious diseases, 12(6), pp.488-496.

Peters, W. ed., 2013. Antimalarial Drugs I: Biological Background, Experimental Methods, and Drug Resistance (Vol. 68). Springer.

Haynes, R.K., Cheu, K.W., Chan, H.W., Wong, H.N., Li, K.Y., Tang, M.M.K., Chen, M.J., Guo, Z.F., Guo, Z.H., Sinniah, K. and Witte, A.B., 2012. Interactions between artemisinins and other antimalarial drugs in relation to the cofactor model—a unifying proposal for drug action. ChemMedChem, 7(12), pp.2204-2226.

Movellan, J., Urbán, P., Moles, E., Jesús, M., Sierra, T., Serrano, J.L. and Fernandez-Busquets, X., 2014. Amphiphilic dendritic derivatives as nanocarriers for the targeted delivery of antimalarial drugs. Biomaterials, 35(27), pp.7940-7950.

Jover, J.A., Leon, L., Pato, E., Loza, E., Rosales, Z., Matias, M.A., Mendez-Fernandez, R., Díaz-Valle, D., Benitez-Del-Castillo, J.M. and Abasolo, L., 2012. Long-term use of antimalarial drugs in rheumatic diseases. Clinical and Experimental Rheumatology-Incl Supplements, 30(3), p.380.