One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas, X-ray, and In Silico ADME/Tox Profiling Studies

Hegira Ramírez,Mario V Capparelli,Esteban Fernandez-Moreira,Jorge Ángel,Katiuska Charris,Jaime Charris,Benjamín Nogueda-Torres

doi:10.3390/molecules26226977

Abstract

Several methoxybenzo[h]quinoline-3-carbonitrile analogs were designed and synthesized in a repositioning approach to developing compounds with anti-prostate cancer and anti-Chagas disease properties. The compounds were synthesized through a sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-tetralone in the presence of ammonium acetate and acetic acid (catalytic). The effect of the one-pot method on the generation of the target product has been studied. The compounds were in vitro screened against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and were most effective at showing a better activity profile than nifurtimox and benznidazole (reference drugs). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds was reported. In addition, X-ray data for the compound 2-Amino-5,6-dihydro-4-(3-hydroxy-4-methoxy-phenyl)-8-methoxybenzo[h]quinoline-3-carbonitrile 6 was being reported. Spectral (IR, NMR, and elemental analyses) data on all final compounds were consistent with the proposed structures.

Highlights

Cancer and tropical diseases caused by protozoa are two dissimilar illnesses that manifest themselves through different symptoms
A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help to describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds is reported
An environmentally-friendly and moderately efficient method for the preparation of 2–aminobenzo[h]quinoline derivatives were successfully developed via arylaldehyde, 1-tetralone, malononitrile, and ammonium acetate i2n. eRtheasunoltlsbaynthdeD“tihsrceues-csoiomnponent” domino reaction under the thermal, microwave, and ua2sl.1t2r.a-Sasmoinuitnnhode-sm4is-aeortfhy2ol--d3ao-mclyoiagnnioeo-s5p[,y62r3-id,d2ii4hn]ye.dsIrt,oihn-a4dd-e(n3fuoor[rt1h,42e--rhbby]pedeyrnorixrdyeip-n4oesrotrceod3u-tmlhdaebttheaoncxaoylnopsghtresunycysttlee)d-muss, isnugcha omneet-hpooxtycboeunpzoli[nhg]-rqeuaicntoiolinneu-s3i-ncgarmboicnriotrwilaevDe earcitvivataitvioesn,(4o—r u1n5d)er solvent-free conditions and cTonhveentsioynnathl heesiastingofmo2d–ea[m25i,n26o]b. eHnozwoe[hv]eqr,utihneodlienveelopdmereinvtaotifvaegsenehraasl anbdeefnfi- largely cinievnetsstyignathteetdic; sotrnaetegoyf ttoheobmtaions2t –raempionrotpeydripdirnoecefussseeds wwiaths arseilxa-tmedemtboeraedclrainsgsiocf athdedition o

Summary

Introduction

Cancer and tropical diseases caused by protozoa are two dissimilar illnesses that manifest themselves through different symptoms. They share similar metabolic requirements related to a high proliferation rate [1]. Cancer is the second leading cause of death globally after ischemic heart disease and stroke. In 2018, there were an estimated 18.1 million new cases, and 9.6 million deaths from cancer, as per data registered by the World Health Organization (WHO) [2]. Chemotherapy has played a central role in the clinical treatment of cancer, and numerous anticancer agents have been approved for this purpose [4,5,6,7]

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