DOI: 10.1128/aac.00420-10. Activity of a Trisubstituted Pyrrole in Inhibiting Sporozoite Invasion and Blocking Malaria Infection

Activity of a Trisubstituted Pyrrole in Inhibiting Sporozoite Invasion and Blocking Malaria Infection

10.1128/aac.00420-10

Crossref journal-article

American Society for Microbiology

Antimicrobial Agents and Chemotherapy (235)

Abstract

ABSTRACT Malaria infection is initiated by Plasmodium sporozoites infecting the liver. Preventing sporozoite infection would block the obligatory first step of the infection and perhaps reduce disease severity. In addition, such an approach would decrease P lasmodium vivax hypnozoite formation and therefore disease relapses. Here we describe the activity of a trisubstituted pyrrole, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H-pyrrol-3-yl] pyridine, in inhibiting motility, invasion, and consequently infection by P. berghei sporozoites. In tissue culture, the compound was effective within the first 3 h of sporozoite addition to HepG2 cells. In vivo , intraperitoneal administration of the compound significantly inhibited liver-stage parasitemia in P. yoelii sporozoite-infected mice and prevented the appearance of blood-stage parasites. P. berghei sporozoites lacking the parasite cGMP-dependent protein kinase, the primary target of the compound in erythrocyte-stage parasites, remained infectious to HepG2 cells and sensitive to the drug. These results suggest that the drug has an additional target(s) in sporozoites. We propose that drugs that inhibit sporozoite infection offer a feasible approach to malaria prophylaxis.

Bibliography

Panchal, D., & Bhanot, P. (2010). Activity of a Trisubstituted Pyrrole in Inhibiting Sporozoite Invasion and Blocking Malaria Infection. Antimicrobial Agents and Chemotherapy, 54(10), 4269â4274.

Authors 2

Dhruv Panchal (first)
Purnima Bhanot (additional)

References 25 Referenced 29

10.1016/S0140-6736(05)67669-6
Beier, J. C., M. S. Beier, J. A. Vaughan, C. B. Pumpuni, J. R. Davis, and B. H. Noden. 1992. Sporozoite transmission by Anopheles freeborni and Anopheles gambiae experimentally infected with Plasmodium falciparum. J. Am. Mosq. Control Assoc.8:404-408. / J. Am. Mosq. Control Assoc. (1992)
10.1016/S0020-7519(01)00265-X
10.1371/journal.pmed.0030513
10.1128/AAC.50.5.1731-1737.2006
10.1371/journal.pone.0002732
10.1017/S0031182000074746
10.1016/j.molbiopara.2005.10.020
Falae, A., A. Combe, A. Anburaj, T. G. Carvalho, R. Menard, and P. Bhanot. 2009. The role of Plasmodium berghei cGMP dependent protein kinase in late liver stage development. J. Biol. Chem.285:3282-3288. / J. Biol. Chem. (2009)
10.1128/AAC.42.10.2731
Gurnett, A. M., P. A. Liberator, P. M. Dulski, S. P. Salowe, R. G. Donald, J. W. Anderson, J. Wiltsie, C. A. Diaz, G. Harris, B. Chang, S. J. Darkin-Rattray, B. Nare, T. Crumley, P. S. Blum, A. S. Misura, T. Tamas, M. K. Sardana, J. Yuan, T. Biftu, and D. M. Schmatz. 2002. Purification and molecular characterization of cGMP-dependent protein kinase from apicomplexan parasites. A novel chemotherapeutic target. J. Biol. Chem.277:15913-15922. / A novel chemotherapeutic target. J. Biol. Chem. (2002)
10.1128/AAC.01043-07
10.1038/nrd2960
10.1371/journal.pbio.0060139
10.1128/IAI.73.7.4363-4369.2005
10.1371/journal.ppat.1000599
10.1128/AAC.46.2.300-307.2002
10.1371/journal.pone.0005078
10.1016/0035-9203(91)90012-N
10.1371/journal.ppat.0020105
Renia, L., F. Miltgen, Y. Charoenvit, T. Ponnudurai, J. P. Verhave, W. E. Collins, and D. Mazier. 1988. Malaria sporozoite penetration. A new approach by double staining. J. Immunol. Methods112:201-205. / A new approach by double staining. J. Immunol. Methods (1988)
10.1016/0166-6851(85)90058-1
10.1128/EC.00186-09
10.1007/BF00932618
10.1084/jem.154.4.1225

Dates

Type	When
Created	15 years, 1 month ago (July 20, 2010, 12:38 a.m.)
Deposited	3 years, 6 months ago (Feb. 21, 2022, 3:16 p.m.)
Indexed	2 months, 3 weeks ago (June 13, 2025, 3:47 a.m.)
Issued	14 years, 11 months ago (Oct. 1, 2010)
Published	14 years, 11 months ago (Oct. 1, 2010)
Published Print	14 years, 11 months ago (Oct. 1, 2010)

Funders 0

None

BibTeX

@article{Panchal_2010, title={Activity of a Trisubstituted Pyrrole in Inhibiting Sporozoite Invasion and Blocking Malaria Infection}, volume={54}, ISSN={1098-6596}, url={http://dx.doi.org/10.1128/aac.00420-10}, DOI={10.1128/aac.00420-10}, number={10}, journal={Antimicrobial Agents and Chemotherapy}, publisher={American Society for Microbiology}, author={Panchal, Dhruv and Bhanot, Purnima}, year={2010}, month=oct, pages={4269–4274} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        6,
        13
      ]
    ],
    "date-time": "2025-06-13T07:47:53Z",
    "timestamp": 1749800873507
  },
  "reference-count": 25,
  "publisher": "American Society for Microbiology",
  "issue": "10",
  "license": [
    {
      "start": {
        "date-parts": [
          [
            2010,
            10,
            1
          ]
        ],
        "date-time": "2010-10-01T00:00:00Z",
        "timestamp": 1285891200000
      },
      "content-version": "tdm",
      "delay-in-days": 0,
      "URL": "https://journals.asm.org/non-commercial-tdm-license"
    }
  ],
  "content-domain": {
    "domain": [
      "journals.asm.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2010,
        10
      ]
    ]
  },
  "abstract": "<jats:title>ABSTRACT</jats:title>\n          <jats:p>\n            Malaria infection is initiated by\n            <jats:italic>Plasmodium</jats:italic>\n            sporozoites infecting the liver. Preventing sporozoite infection would block the obligatory first step of the infection and perhaps reduce disease severity. In addition, such an approach would decrease\n            <jats:italic>P</jats:italic>\n            <jats:italic>lasmodium</jats:italic>\n            <jats:italic>vivax</jats:italic>\n            hypnozoite formation and therefore disease relapses. Here we describe the activity of a trisubstituted pyrrole, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H-pyrrol-3-yl] pyridine, in inhibiting motility, invasion, and consequently infection by\n            <jats:italic>P. berghei</jats:italic>\n            sporozoites. In tissue culture, the compound was effective within the first 3 h of sporozoite addition to HepG2 cells.\n            <jats:italic>In vivo</jats:italic>\n            , intraperitoneal administration of the compound significantly inhibited liver-stage parasitemia in\n            <jats:italic>P. yoelii</jats:italic>\n            sporozoite-infected mice and prevented the appearance of blood-stage parasites.\n            <jats:italic>P. berghei</jats:italic>\n            sporozoites lacking the parasite cGMP-dependent protein kinase, the primary target of the compound in erythrocyte-stage parasites, remained infectious to HepG2 cells and sensitive to the drug. These results suggest that the drug has an additional target(s) in sporozoites. We propose that drugs that inhibit sporozoite infection offer a feasible approach to malaria prophylaxis.\n          </jats:p>",
  "DOI": "10.1128/aac.00420-10",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2010,
        7,
        20
      ]
    ],
    "date-time": "2010-07-20T04:38:52Z",
    "timestamp": 1279600732000
  },
  "page": "4269-4274",
  "update-policy": "http://dx.doi.org/10.1128/asmj-crossmark-policy-page",
  "source": "Crossref",
  "is-referenced-by-count": 29,
  "title": "Activity of a Trisubstituted Pyrrole in Inhibiting Sporozoite Invasion and Blocking Malaria Infection",
  "prefix": "10.1128",
  "volume": "54",
  "author": [
    {
      "given": "Dhruv",
      "family": "Panchal",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Department of Microbiology and Molecular Genetics, UMDNJ\u2014New Jersey Medical School, Newark, New Jersey 07103"
        }
      ]
    },
    {
      "given": "Purnima",
      "family": "Bhanot",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Microbiology and Molecular Genetics, UMDNJ\u2014New Jersey Medical School, Newark, New Jersey 07103"
        }
      ]
    }
  ],
  "member": "235",
  "reference": [
    {
      "key": "e_1_3_2_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0140-6736(05)67669-6"
    },
    {
      "key": "e_1_3_2_3_2",
      "first-page": "404",
      "volume": "8",
      "year": "1992",
      "unstructured": "Beier, J. C., M. S. Beier, J. A. Vaughan, C. B. Pumpuni, J. R. Davis, and B. H. Noden. 1992. Sporozoite transmission by Anopheles freeborni and Anopheles gambiae experimentally infected with Plasmodium falciparum. J. Am. Mosq. Control Assoc.8:404-408.",
      "journal-title": "J. Am. Mosq. Control Assoc."
    },
    {
      "key": "e_1_3_2_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0020-7519(01)00265-X"
    },
    {
      "key": "e_1_3_2_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.pmed.0030513"
    },
    {
      "key": "e_1_3_2_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/AAC.50.5.1731-1737.2006"
    },
    {
      "key": "e_1_3_2_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.pone.0002732"
    },
    {
      "key": "e_1_3_2_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1017/S0031182000074746"
    },
    {
      "key": "e_1_3_2_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.molbiopara.2005.10.020"
    },
    {
      "key": "e_1_3_2_10_2",
      "first-page": "3282",
      "volume": "285",
      "year": "2009",
      "unstructured": "Falae, A., A. Combe, A. Anburaj, T. G. Carvalho, R. Menard, and P. Bhanot. 2009. The role of Plasmodium berghei cGMP dependent protein kinase in late liver stage development. J. Biol. Chem.285:3282-3288.",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_2_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/AAC.42.10.2731"
    },
    {
      "key": "e_1_3_2_12_2",
      "first-page": "15913",
      "volume": "277",
      "year": "2002",
      "unstructured": "Gurnett, A. M., P. A. Liberator, P. M. Dulski, S. P. Salowe, R. G. Donald, J. W. Anderson, J. Wiltsie, C. A. Diaz, G. Harris, B. Chang, S. J. Darkin-Rattray, B. Nare, T. Crumley, P. S. Blum, A. S. Misura, T. Tamas, M. K. Sardana, J. Yuan, T. Biftu, and D. M. Schmatz. 2002. Purification and molecular characterization of cGMP-dependent protein kinase from apicomplexan parasites. A novel chemotherapeutic target. J. Biol. Chem.277:15913-15922.",
      "journal-title": "A novel chemotherapeutic target. J. Biol. Chem."
    },
    {
      "key": "e_1_3_2_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/AAC.01043-07"
    },
    {
      "key": "e_1_3_2_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nrd2960"
    },
    {
      "key": "e_1_3_2_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.pbio.0060139"
    },
    {
      "key": "e_1_3_2_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/IAI.73.7.4363-4369.2005"
    },
    {
      "key": "e_1_3_2_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.ppat.1000599"
    },
    {
      "key": "e_1_3_2_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/AAC.46.2.300-307.2002"
    },
    {
      "key": "e_1_3_2_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.pone.0005078"
    },
    {
      "key": "e_1_3_2_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0035-9203(91)90012-N"
    },
    {
      "key": "e_1_3_2_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.ppat.0020105"
    },
    {
      "key": "e_1_3_2_22_2",
      "first-page": "201",
      "volume": "112",
      "year": "1988",
      "unstructured": "Renia, L., F. Miltgen, Y. Charoenvit, T. Ponnudurai, J. P. Verhave, W. E. Collins, and D. Mazier. 1988. Malaria sporozoite penetration. A new approach by double staining. J. Immunol. Methods112:201-205.",
      "journal-title": "A new approach by double staining. J. Immunol. Methods"
    },
    {
      "key": "e_1_3_2_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0166-6851(85)90058-1"
    },
    {
      "key": "e_1_3_2_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/EC.00186-09"
    },
    {
      "key": "e_1_3_2_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/BF00932618"
    },
    {
      "key": "e_1_3_2_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1084/jem.154.4.1225"
    }
  ],
  "container-title": "Antimicrobial Agents and Chemotherapy",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://journals.asm.org/doi/pdf/10.1128/AAC.00420-10",
      "content-type": "application/pdf",
      "content-version": "vor",
      "intended-application": "text-mining"
    },
    {
      "URL": "https://journals.asm.org/doi/pdf/10.1128/AAC.00420-10",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        2,
        21
      ]
    ],
    "date-time": "2022-02-21T20:16:58Z",
    "timestamp": 1645474618000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://journals.asm.org/doi/10.1128/AAC.00420-10"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2010,
        10
      ]
    ]
  },
  "references-count": 25,
  "journal-issue": {
    "issue": "10",
    "published-print": {
      "date-parts": [
        [
          2010,
          10
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1128/AAC.00420-10"
  ],
  "URL": "http://dx.doi.org/10.1128/AAC.00420-10",
  "relation": {},
  "ISSN": [
    "0066-4804",
    "1098-6596"
  ],
  "subject": [],
  "container-title-short": "Antimicrob Agents Chemother",
  "published": {
    "date-parts": [
      [
        2010,
        10
      ]
    ]
  },
  "assertion": [
    {
      "value": "2010-03-29",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2010-07-12",
      "order": 1,
      "name": "accepted",
      "label": "Accepted",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2010-10-01",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}