Aloysius T. Nchinda

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2Rγ^null Mouse Model of Malaria

Journal of Medicinal Chemistry (2018)

Aloysius T. Nchinda Claire Le Manach Tanya Paquet Diego Gonzàlez Cabrera Kathryn J. Wicht

Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.

ADME

10.1021/acs.jmedchem.8b00382

Cite

Citations (19)

Development of Domain‐Selective Angiotensin I‐Converting Enzyme Inhibitors

Annals of the New York Academy of Sciences (2005)

Pierre Redelinghuys Aloysius T. Nchinda Edward D. Sturrock

Somatic angiotensin-converting enzyme (ACE) is an essential component of the renin-angiotensin system and consequently plays a key role in blood pressure and electrolyte homeostasis. Thus, ACE inhibitors are widely used in the treatment of cardiovascular disease, causing a decrease in the production of angiotensin II and an increase in the circulating vasodilator bradykinin. The ectodomain of ACE consists of two parts (N and C domains), each bearing an active site that differs in substrate and inhibitor specificity. Advances in the elucidation of the functional roles of these two domains and an expanded view of the renin-angiotensin system underscore the need for the next generation of domain-selective inhibitors with improved pharmacologic profiles. Moreover, recent breakthroughs in determining the crystal structure of testis ACE (identical to the C domain) and its homologue ACE2 provide new mechanistic insights into the interactions of ACE inhibitors and substrates with active site pockets. This review summarizes the structural basis and recent synthetic chemistry approaches to the development of novel domain-selective inhibitors.

Ectodomain

Homeostasis

10.1196/annals.1352.035

Cite

Citations (30)

Structure–Activity Relationship Studies of Orally Active Antimalarial 3,5-Substituted 2-Aminopyridines

Journal of Medicinal Chemistry (2012)

Diego Gonzàlez Cabrera Frédèric Douelle Yassir Younis Tzu‐Shean Feng Claire Le Manach

In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.

hERG

Aminopyridines

Cardiotoxicity

Plasmodium berghei

Structure–activity relationship

Primaquine

10.1021/jm301476b

Cite

Citations (38)

Chemical studies of selected chromone derivatives

Aloysius T. Nchinda

Chromone

Source

Cite

Citations (1)

2,4-Diaminothienopyrimidines as Orally Active Antimalarial Agents

Journal of Medicinal Chemistry (2014)

Diego Gonzàlez Cabrera Claire Le Manach Frédèric Douelle Yassir Younis Tzu‐Shean Feng

A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.

hERG

Plasmodium berghei

Structure–activity relationship

10.1021/jm401760c

Cite

Citations (35)

1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in Mycobacterium tuberculosis

Journal of Medicinal Chemistry (2021)

Lutete Peguy Khonde Rudolf Müller Grant A. Boyle Virsinha Reddy Aloysius T. Nchinda

Phenotypic whole cell high-throughput screening of a ∼150,000 diverse set of compounds against Mycobacterium tuberculosis (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide 1 as a moderately active hit. Structure–activity relationship (SAR) studies demonstrated a clear scope to improve whole cell potency to MIC values of <0.5 μM, and a plausible pharmacophore model was developed to describe the chemical space of active compounds. Compounds are bactericidal in vitro against replicating Mtb and retained activity against multidrug-resistant clinical isolates. Initial biology triage assays indicated cell wall biosynthesis as a plausible mode-of-action for the series. However, no cross-resistance with known cell wall targets such as MmpL3, DprE1, InhA, and EthA was detected, suggesting a potentially novel mode-of-action or inhibition. The in vitro and in vivo drug metabolism and pharmacokinetics profiles of several active compounds from the series were established leading to the identification of a compound for in vivo efficacy proof-of-concept studies.

INHA

Mode of Action

10.1021/acs.jmedchem.1c00837

Cite

Citations (18)

Chromone Studies. Part 11. Synthesis and Electron‐Impact Mass Spectrometric Study of Granulosin and Side‐Chain Analogues.

ChemInform (2003)

Perry T. Kaye Aloysius T. Nchinda Christopher A. Gray

Abstract For Abstract see ChemInform Abstract in Full Text.

Chromone

Side chain

10.1002/chin.200301205

Cite

Citations (1)

Crystal Structure of the N Domain of Human Somatic Angiotensin I-converting Enzyme Provides a Structural Basis for Domain-specific Inhibitor Design

Journal of Molecular Biology (2006)

Hazel Corradi Sylva L. U. Schwager Aloysius T. Nchinda Edward D. Sturrock K. Ravi Acharya

Linker

Cooperativity

Lisinopril

10.1016/j.jmb.2006.01.048

Cite

Citations (162)

Lerisetron Analogues with Antimalarial Properties: Synthesis, Structure–Activity Relationship Studies, and Biological Assessment

ACS Omega (2020)

Rudolf Mueller Virsinha Reddy Aloysius T. Nchinda Fanuel M. Mebrahtu Dale Taylor

A phenotypic whole cell high-throughput screen against the asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron 1 (IC50 NF54 = 0.81 μM) and its methyl-substituted analogue 2 (IC50 NF54 = 0.098 μM). A medicinal chemistry hit to lead effort led to the identification of chloro-substituted analogue 3 with high potency against the drug-sensitive NF54 (IC50 NF54 = 0.062 μM) and multidrug-resistant K1 (IC50 K1 = 0.054 μM) strains of the human malaria parasite Plasmodium falciparum. Compounds 2 and 3 gratifyingly showed in vivo efficacy in both Plasmodium berghei and P. falciparum mouse models of malaria. Cardiotoxicity risk as expressed in strong inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was identified as a major liability to address. This led to the synthesis and biological assessment of around 60 analogues from which several compounds with improved antiplasmodial potency, relative to the lead compound 3, were identified.

hERG

Benzimidazole

IC50

Plasmodium berghei

10.1021/acsomega.0c00327

Cite

Citations (15)

Novel ketomethylene inhibitors of angiotensin I-converting enzyme (ACE): inhibition and molecular modelling

Biological Chemistry (2006)

Pierre Redelinghuys Aloysius T. Nchinda Kelly Chibale Edward D. Sturrock

Inhibition of angiotensin I-converting enzyme (ACE) has become an effective strategy in the treatment of hypertension and cardiovascular disease. Keto-ACE, a previously described C-domain selective ACE inhibitor, was used as the basis for the design, synthesis and molecular modelling of a series of novel ketomethylene derivatives for which ACE inhibition profiles and structural characterisation are reported. Ki determinations indicated that the introduction of a bulky aromatic tryptophan at the P2′ position of keto-ACE significantly increased selectivity for the C-domain, while an aliphatic P2 Boc group conferred N-domain selectivity. These data were supported by the potential energies of the compounds docked with the C- and N-domains of ACE.

10.1515/bc.2006.061

Cite

Citations (12)