In Silico Study, Synthesis, Characterisation And Cytotoxicity Activity Of New Chalcone, Pyrazoline And Pyrimidine Derivatives

Three new series of novel chalcone derivatives with promising anti-cancer activity were studied which are two series of tri-chalcone derivatives S1(1-7) and S2(1-7) and a series of mono-chalcone derivatives S3(1-7). Another three series of pyrazoline Ai-Aiii and pyrimidine Bi-Biii from mono-chalcone were also studied by AutoDock 4.2.6. The intermolecular interactions and binding energies of the proposed compounds were determined to be synthesised and characterized. The best compounds were selected for further investigation by MD simulation using AMBER 14. The following compounds of chalcone derivatives S1-1, S1-2, S2-1, S2-2, S3-1, S3-(3-5), pyrazoline derivatives Ai-Aiii and pyrimidine Bi-Biii from mono-chalcone S3-(1,3-5) demonstrated the highest binding affinity for the interaction with the active EGFR binding site. These selected chalcones, pyrazoline and pyrimidine derivatives were synthesised to test their cytotoxicity activity against breast cancer cell lines and EGFR inhibitory activity. Synthesis of the chalcone derivatives was performed via a Claisen-Schmidt condensation while the ring-closing of mono-chalcones formed the pyrazoline and pyrimidine derivatives. The chemical structures of the synthesised compounds were confirmed using spectroscopic techniques such as FTIR, 1H NMR, 13C NMR and elemental analysis (CHN analysis). Antiproliferative activity of the synthesised compounds against breast cancer cell lines (MCF-7 and MDA-MB-231) were evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT)

Novel mitochondrial electron transport-chain inhibitors as potencial antimalarial agents

Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2010The bc1 complex is an attractive a validated drug target in the fight against malaria. The mitochondrial electron transport-chain, in which this complex is involved, is fundamental in Plasmodium sp.. The parasites do not possess the requested enzymatic machinery to salvage pyrimidines from their metabolism and, therefore, have to perform de novo pyrimidine biosynthesis to enable their survival. Blockage of this pathway leads to their death. The present work focused on the development of novel inhibitors with structural similarity to known bc1 complex antagonists. Also, this work aimed at delivering novel leads for drug development. 4-Pyridonimines with extended lipophilic side chains showed potential as isosteric replacements for 4(1H)-pyridones. The structure of those compounds was derived from structure-based design and they were active in vitro against P. falciparum. The most active compound presented an IC50 of ca. 1 μM, and the mode of action was hypothesized through docking studies. A series of 4-quinolonimines was also prepared. Those presented enhanced antiplasmodial activity in comparison to the previous set of compounds, with IC50s ranging from 0.5 to 1 μM. These also showed outstanding activity against the liver stage of P. berghei. Despite the mechanism of action not being clear at the moment, the compounds demonstrated to bind to hematin. However, the docking studies in the Qo site of the bc1 complex also showed a good fit of the compounds. Flavones were also synthesized with the aim of optimizing the antiplasmodial activity of stigmatellin. All compounds showed modest activity against both blood and liver stages, with the most active compound presenting an IC50 of 6 μM against P. falciparum W2 strain. Finally, the virtual screening study that was performed allowed the discovery of novel scaffolds with antiplasmodial activity. A combination of ligand- and receptor-based approaches was successful in retrieving 7 active compounds out of the 23 that were purchased. One of them presented an IC50 of 2 μM in vitro.O complexo bc1 é um alvo terapêutico atractivo e validado na luta contra a malária. A cadeia transportadora de electrões, em que este complexo está envolvido, é fundamental em parasitas do género Plasmodium sp.. Os parasitas não possuem as enzimas necessárias para reciclar as pirimidinas vindas do metabolismo e, por isso, necessitam de sintetizá-las de novo, de forma a permitir a sobrevivência do parasita. O bloqueio desta via metabólica conduz à morte sua morte. O presente trabalho incidiu no desenvolvimento de novos inibidores com semelhança estrutural a antagonistas conhecidos do complexo bc1. De igual forma, este trabalho focou-se na descoberta de novos protótipos para o desenvolvimento de novos antimaláricos. As 4-piridoniminas com cadeias lipofílicas longas mostraram potencial como isósteros das 4(1H)-piridonas. A estrutura dos primeiros foi derivada de estudos de docking molecular e apresentaram actividade in vitro contra P. falciparum. O composto mais activo possui um IC50 de aproximadamente 1 μM e o seu modo de acção foi posto em hipótese por docking molecular. Uma série de 4-quinolomininas foi também preparada. Estas mostraram ser mais activas que a série de compostos anteriores, com IC50 entre 0,5 e 1 μM, tendo mostrado também excelente actividade contra a fase hepática de P. berghei. Apesar do mecanismo de acção não ser claro neste momento, os compostos mostraram ligar-se à hematina. Contudo, os estudos de docking molecular no sítio Qo do complexo bc1 podem, igualmente, justificar as actividades obtidas. Foi sintetizada uma série de flavonas com o intuito de optimizar a actividade antiplasmódica da estigmatelina. Todos os compostos obtidos mostraram actividade modesta contra as fases sanguínea e hepática, com o composto mais activo a apresentar um IC50 de 6 μM contra a estirpe W2 de P. falciparum. Finalmente, o estudo de screening virtual que foi efectuado permitiu a descoberta de novos núcleos com actividade antiplasmódica. A combinação de um método aplicando, de forma faseada, a informação de ligandos e do receptor resultou na obtenção de 7 compostos activos, de um total de 23 comprados. Um dos compostos apresentou um IC50 de 2 μM in vitro.Fundação para a Ciência e a Tecnologia: bolsa de doutoramento SFRH/BD/30689/2006; projecto PTDC/SAU-FCT/098734/2008Fundação para a Ciência e Tecnologia (FCT), SFRH/BD/30689/2006; projecto PTDC/SAU-FCT/098734/200

Cloning, expression, purification and drug targeting of Plasmodium falciparum hypoxanthine guanine xanthine phosphoribosyltransferase (HGXPRT)

Includes bibliographical references.The research concerns sub-cloning the gene for HGXPRT from Plasmodium falciparum from a vector with a His-tag facility to one without, expression of the protein in E. coli, and purification. On an analytical scale (40 ml culture), a purification procedure was developed that involves extraction of contaminating proteins by anion exchange chromatography (HGXPRT does not bind under the conditions used), followed by Reactive Red 120 agarose affinity chromatography

Pharmacotherapeutics applications and chemistry of chalcone derivatives

Chalcones have been well examined in the extant literature and demonstrated antibacterial, antifungal, anti-inflammatory, and anticancer properties. A detailed evaluation of the purported health benefits of chalcone and its derivatives, including molecular mechanisms of pharmacological activities, can be further explored. Therefore, this review aimed to describe the main characteristics of chalcone and its derivatives, including their method synthesis and pharmacotherapeutics applications with molecular mechanisms. The presence of the reactive α,β-unsaturated system in the chalcone’s rings showed different potential pharmacological properties, including inhibitory activity on enzymes, anticancer, anti-inflammatory, antibacterial, antifungal, antimalarial, antiprotozoal, and anti-filarial activity. Changing the structure by adding substituent groups to the aromatic ring can increase potency, reduce toxicity, and broaden pharmacological action. This report also summarized the potential health benefits of chalcone derivatives, particularly antimicrobial activity. We found that several chalcone compounds can inhibit diverse targets of antibiotic-resistance development pathways; therefore, they overcome resistance, and bacteria become susceptible to antibacterial compounds. A few chalcone compounds were more active than conventional antibiotics, like vancomycin and tetracycline. On another note, a series of pyran-fused chalcones and trichalcones can block the NF-B signaling complement system implicated in inflammation, and several compounds demonstrated more potent lipoxygenase inhibition than NSAIDs, such as indomethacin. This report integrated discussion from the domains of medicinal chemistry, organic synthesis, and diverse pharmacological applications, particularly for the development of new anti-infective agents that could be a useful reference for pharmaceutical scientists

Chalcones: Synthetic Chemistry Follows Where Nature Leads

Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for exploitation for new drug discovery, justifying the title of this article. However, the focus remains on critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their interactions at the biomolecular level where appropriate, and revealing their possible mechanisms of action

Use of Structure-And Ligand-Based Drug Design Tools for the Discovery of Small Molecule Inhibitors of Cysteine Proteases for the Treatment of Malaria and Sars Infection

A wide array of molecular modeling tools were utilized to design and develop inhibitors against cysteine protease of P. Falciparum Malaria and Severe Acute Respiratory Syndrome (SARS). A number of potent inhibitors were developed against cysteine protease and hemoglobinase of P. falciparum , referred as Falcipains (FPs), by the structure-based virtual screening of the focused libraries enriched in soft-electrophiles containing compounds. Twenty one diverse, non-peptidic, low micromolar hits were identified. A combined data mining and combinatorial library synthesis approach was performed to discover analogs of virtual screening hits and establish the structure-activity relationships (SAR). However, the resulting SAR of the identified hits was unusually steep in some cases and could not be explained by a traditional analysis of the interactions (electrostatics, van der Waals or H-bond). To gain insights, a statistical thermodynamic analysis of explicit solvent in the ligand binding domain of FP-2 and FP-3 was performed that explained some of the complex trends in the SAR. Furthermore, the moderate potency of a subset of FP-2 hits was elucidated using quantum mechanics calculations that shoreduced reactivity of the electrophilic center of these hits. In addition, solvent thermodynamics and reactivity analysis also helped to elucidate the complex trends in SAR of peptidomimetic inhibitors of FP-2 and FP-3 synthesized in our laboratory. Multi nanosecond explicit solvent molecular dynamics simulations were carried out using the docking poses of the known inhibitors in the binding site of SARS-3CLpro, a cysteine protease important for replication of SARS virus, to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Analysis of the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts against cysteine protease (3CLpro) of SARS

Curcumin-related hybrid compounds as potential antimalarial agents : design, synthesis, mechanistic investigations, biological evaluation and pharmacokinetic studies

Includes bibliographical references.Malaria remains one of the most devastating tropical diseases, with staggering infection and mortality statistics. Over 200 million clinical cases of malaria (resulting in 1 - 3 million deaths) are reported annually. Africa bears the greatest burden of this disease. with the vast majority of malaria cases (>85%). and malaria-related deaths (>90%). being reported in sub-Saharan Africa. The main challenge to malaria control has been the development of clinically significant resistance Of the parasite to most known antimalarial drugs. This suggests that the development of new, highly efficadous drugs and/or treatment regimens for the management of malaria remains a key priority. This study applied molecular hybridization as a strategy in the development of novel potential antimalarial agents. The aim was to try and identify novel hybrid compounds containing scaffolds that are structurally related to the natural product curcumin, and which exhibit in vitro and in vivo antimalarial activity. Part of the study involved investigations into the pharmacokinetics and possible antimalarial mechanisms of action of selected target compounds

Synthesis and computer-assisted design of mitochondrial electron transport-chain inhibitors as antimalarial agents

Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2014Malaria remains a critical global health problem, with terrible social and economic consequences in countries where this disease is endemic. The problem is exacerbated by the emergence and spread of parasites that are resistant to well-established antimalarial drugs. As a result, there is an urgent need for novel drugs, preferably acting on under exploited parasite targets in order to overcome clinical resistance. Cytochrome bc1 complex is a crucial element in the mitochondrial respiratory chain, being indispensable for the survival of several species of Plasmodia that cause malaria and, therefore, it is a promising target for antimalarial drug development. Moreover, in the absence of a crystal structure for the P. falciparum bc1 complex, key structural and mechanistic information has been inferred from analogous mammalian, bacterial and yeast bc1 systems. In the present work, a molecular docking study based on the most recently obtained X-ray structure of the Saccharomyces cerevisiae bc1 complex (PDB code: 3CX5) and using several reported inhibitors with experimentally determined IC50 values against the Plasmodium falciparum bc1 complex is presented. This Qo model was also used to search the drug-like database included in the MOE package for novel potential bc1 complex inhibitors allowing to obtain five compounds with demonstrated activity against the chloroquine-resistant W2 strain of P. falciparum. Moreover, the most active compounds were also active against the atovaquone-resistant P. falciparum FCR3 strain and S.cerevisiae. Furthermore, considering that a reliable three-dimensional structure of this Pf enzymatic complex is essential for successful drug design and having in mind the increasing interest in obtaining potential antimalarial drugs that can act in this target, a homology model of cytochrome bc1 Qo binding site was further developed based on yeast crystallographic structure. Additionally, a library containing several structurally diverse aurone and azaaurone derivatives were also synthesized and tested for their antimalarial activity. The aurone derivatives synthesized showed to be moderate active with IC50 values in the low micromolar range while de azaaurone analogous presented much higher potency with some compounds being active in the nanomolar range. Despite the mechanism of action of these two classes of compounds is still not very clear, this study highlight the usefulness of aurones and azaaurones to be derivatized in order to rapidly deliver lead compounds for further optimization and also the potential of these two scaffolds as promising antimalarial compounds.A malária continua a ser um grave problema de saúde, com enormes consequências sociais e económicas que afectam os países onde esta doença é endémica. Este problema tem vindo a crescer devido ao agravamento do aparecimento de parasitas resistentes aos fármacos antimaláricos disponíveis. Apesar da importância geral desta doença, o desenvolvimento de novos fármacos tem sido negligenciado pela indústria farmacêutica nos países industrializados. Deste modo, existe uma necessidade urgente de obter novos fármacos, de preferência que actuem em alvos menos explorados, de modo a se poder superar todos os problemas relacionados com a resistência. Nos últimos anos o esforço para desenvolver novos fármacos tem vindo a aumentar sendo que várias parcerias entre a indústria e a academia têm mesmo sido formadas. Esta união de esforços permite não só expandir o conhecimento existente acerca de fármacos antimaláricos mas também potenciar o progresso na obtenção de novos fármacos. Devido à complexidade do ciclo de vida do parasita, vários alvos têm sido utilizados nos últimos tempos de modo a permitir desenvolver um fármaco que seja eficiente e selectivo para o parasita. Um desses alvos é a cadeia de transporte electrónico que inclue o citocromo bc1. O citocromo bc1 é um elemento crucial para o correcto funcionamento da cadeia de transporte electrónico do parasita. Sendo essencial para a sobrevivência do parasita responsável pela malária, este pode ser considerado um alvo promissor para o desenvolvimento de fármacos antimaláricos. Na ausência de uma estrutura cristalográfica do citocromo bc1 do P. falciparum, toda a informação acerca da sua estrutura e do seu mecanismo tem sido obtida através de estudos desenvolvidos nos seus análogos provenientes de mamíferos, bactérias e leveduras. Neste projecto desenvolveu-se inicialmente um estudo de docking molecular com base na estrutura cristalográfica do citocromo bc1 da levedura Saccharomyces cerevisiae (PDB 3CX5) e utilizando vários inibidores conhecidos com valores de IC50 determinados experimentalmente. Tal permitiu analisar a possibilidade de a estrutura cristalográfica da levedura poder ser utilizada como um bom modelo para o P. falciparum. Mais importante, permitiu também compreender o modo de interacção dos inibidores seleccionados com o centro activo Qo e prever o potencial inibitório destas moléculas. Este modelo foi posteriormente utilizado para se proceder a um estudo de screening virtual utilizando a biblioteca de compostos incluída no programa MOE. Este estudo permitiu obter cinco compostos com actividade antimalárica contra a estirpe W2 resistente à cloroquina. Os compostos mais activos demonstraram também actividade contra a estirpe resistente à atovaquona e contra a levedura. Infelizmente, os estudos biológicos feitos especificamente na cadeia de transporte electrónico não permitiram comprovar que estes compostos actuam definitivamente neste alvo. Tendo em conta a importância de se ter uma estrutura tridimensional adequada para se poder desenhar novos inibidores e considerando o crescente interesse neste alvo, procedeu-se ao desenvolvimento de um modelo por homologia do sítio activo Qo do citocromo bc1 do P. falciparum com base numa estrutura cristalográfica conhecida. Para tal, procedeu-se a um estudo inicial das estruturas cristalográficas deste alvo disponíveis de várias espécies e fez.se a uma comparação exaustiva de modo a seleccionar o melhor modelo. A S. cerevisiae foi a espécie escolhida devido ao grau de homologia entre as duas estruturas homólogas e a resolução da sua estrutura cristalográfica. O modelo por homologia foi desenvolvido utilizando as ferramentas disponíveis no MOE e foi validado utilizando técnicas de docking e screening virtual. Este estudo de screening foi efectuado com base na mesma biblioteca de compostos utilizada anteriormente e permitiu identificar novas moléculas com estruturas químicas bastante interessantes e com potencial para actuar neste alvo. Os dados biológicas destas moléculas não estão ainda disponíveis não permitindo definitivamente validar este modelo por homologia como o modelo mais correcto da estrutura cristalográfica do sítio activo Qo do citocromo bc1 do P. falciparum. Apesar disso, foi feito um enorme avanço em termos de obter uma estrutura tridimensional mais fidedigna deste alvo o que será útil para desenvolver novos inibidores selectivos para o citocromo bc1. Na segunda parte deste trabalho, uma biblioteca de compostos contendo diversos derivados de auronas e azaauronas foi também sintetizada e testada para avaliar a sua actividade antimalárica. As auronas são produtos naturais com actividade antiparasitária já reconhecida. Estes compostos foram primeiramente sintetizados com o objectivo inicial de obter estruturas quimicamente diversas e mais complexas de modo a permitir reconhecer que tipo de alterações permite aumentar o seu potencial antimalárico. Deste modo foram sintetizados vários compostos recorrendo a reacções de acoplamento catalisadas por paládio, como as reacções de Suzuki e Buchwald, devido à facilidade de aumentar rapidamente uma biblioteca de compostos utilizando estes procedimentos. Foram também sintetizados alguns derivados por introdução de uma amina alifática no anel A da aurona de modo a obter bases de Mannich. As moléculas sintetizadas mostraram actividade moderada contra o P. falciparum com valores de IC50 na ordem dos micromolar. Foram feitos ainda vários estudos biológicos com o objectivo de se identificar o modo de acção desta classe de compostos mas tal não foi possível. Novos estudos terão ainda que ser feitos. Os derivados de azaauronas foram obtidos de um modo semelhante ao utilizado para os derivados de auronas. Contudo, neste caso, foi necessário utilizar um método de síntese convergente de modo a se obter os compostos mais eficientemente. Tal deveu-se a problemas associados ao facto de a síntese destes compostos ser mais complexa e menos eficiente que a síntese dos derivados de auronas o que levou não só a uma diminuição do rendimento das reacções mas também a um aumento considerável de produtos secundários e, consequentemente, a um acréscimo na dificuldade em isolar os produtos. Ao contrário dos derivados de auronas, estes novos compostos demonstraram ser bastante mais activos que os seus análogos com valores de IC50 na ordem dos nanomolar. Mais ainda, estes compostos apresentam também citotoxicidade negligenciável. Dado que estes compostos contêm um aceitador de Michael na sua estrutura, foram testados contra a falcipaína-2, uma protease muito importante para a degradação de hemoglobina no vacúolo digestivo do parasita e essencial para a sua sobrevivência. Infelizmente os resultados obtidos indicam que este não é o alvo desta classe de compostos dado que apenas três apresentaram baixo poder inibitório na ordem dos 10 μM. Foi feito ainda um estudo de sinergismo na presença de cloroquina e mefloquina que permitiu demonstrar o potential sinergístico desta classe de potenciais antimaláricos. Mais ainda, a semelhança estrutural destes compostos com as quinolonas, reconhecidos inibidores do citocromo bc1, e os estudos de docking efectuados com base no modelo por homologia desenvolvido anteriormente permite sugerir que seja este o alvo desta classe de compostos. Contudo, estudos biológicos adicionais serão necessários para identificar o modo de acção dos derivados de azaauronas. Finalmente, apesar de o modo de acção destas duas classes de compostos não estar ainda completamente identificado, o estudo desenvolvido demonstra que tanto as auronas como as azaauronas podem ser derivatizadas de modo a se obter novos compostos mais activos. Mais ainda, estas duas classes de compostos podem ser consideradas promissoras no desenvolvimento de fármacos antimaláricos. O estudo desenvolvido pode ser então considerado um passo importante não só na caracterização de um importante alvo terapêutico para a malária mas também na identificação de novas classes de compostos com potencial para ser posteriormente optimizadas de modo a obter novos fármacos antimaláricos com actividade relevante.Fundação para a Ciência e a Tecnologia (FCT, SFRH/BD/61611/2009 e projetos PTDC/SAU-FCT/098734/2008, PTDC/SAU-FAR/118459/2010 e Pest-OE/SAL/UI4013/2011

Molecular Modeling QSAR studies and Synthesis of Novel Azolo Cinnoline Analogs as Antitubercular Agents

A library of two hundred and two compounds containing pyrazolo cinnoline, pyrazole based cinnolines, oxadiazole based cinnolines and imidazothiadiazole based derivatives were designed, and for pre-selection of promising compounds, the compounds were optimized and docked into the active pocket of cytochrome P450 sterol 14α-demethylase from Mycobacterium tuberculosis MtbCYP51 (PDB id: 1EA1) in complex with fluconazole for antimycobacterial studies and into the homology model of Candida albicans CACYP51 for antifungal studies. In principle all docking applications included four steps, i.e. identification and preparation of the receptor site, preparation of the ligands, docking the ligands and evaluation of the docked orientations. According to their docking scores and their interaction with receptor the compounds were selected for synthesis. Based on the docking scores and feasibility of synthesis, forty three compounds were selected, synthesised and screened for its antitubercular against Mycobacterium tuberculosis H37Rv and for its antifungal activity against Candida albicans. All the synthesised compounds have shown good antitubercular and antifungal activity. Among the synthesised candidates the promising antitubercular lead molecules were identified based on their MIC values.The compound 1C (7-chloro derivative of pyrazolo cinnoline series), 6D (6-chloro substituted phenyl derivative of pyrazolo cinnoline), OX-4 (7-chloro and nitro substituted oxadiazole based cinnoline), OX-5 (6-flouro substituted oxadiazole based cinnoline), IMT-6 (6-carboxyl substituted derivative of imidazothiadiazolo based cinnoline), IMT-8 (6-sulphonamido substituted derivative of imidazothiadiazole based cinnoline) and IMT-10 (6-sulphonamido substituted derivative of imidazo thiadiazolo based cinnoline) with excellent antitubercular activity were found to be promising candidate as antitubercular agent. The promising antifungal lead molecules among the synthesized compounds were identified based on their MIC values. The compound 1C (7-chloro derivative of pyrazolo cinnoline), 2C (unsubstituted derivative of pyrazolo cinnoline), 4C (7 nitro derivate of pyrazolo cinnoline), 6D (6-chloro substituted phenyl pyrazolo cinnoline), PY-7(6-chloro derivative of pyrazole based cinnoline), PY-9 (6-nitro substituted pyrazole based cinnoline), OX-1 (3-chloro substituted oxadiazole based cinnoline), OX-2 (3-chloro and hydroxyl substituted oxadiazole based cinnoline), OX-5 (6-flouro substituted oxadiazole based cinnoline),OX-7(4-chloro derivative of oxadiazole), OX-8 (6-chloro and nitro substituted oxadiazole based cinnoline), IMT-12 (un substituted derivative of imidazothiadiazole based cinnoline), IMT-13 (alkyl substituted derivative of imidazothiadiazole based cinnoline) and IMT-14 (6-carboxyl derivative of imidazothiadiazole based cinnoline) with good antifungal activity were found to be promising candidate as antifungal agent. In this study In-silico design was developed to accelerate and assist hit identification, hit-to-lead selection, and lead optimisation. The computational tools were found to advance efficiency and effectiveness of drug discovery process, reduce use of animals and increase predictability of biological action. Computer-aided drug discovery and development utilised here was based on the incerebro-in silico-chemico-biological approach. Thus the molecular modelling studies of azolo cinnoline analogs by targeting the inhibition of enzyme cytochrome P450 14α-sterol demethylase followed by its synthesis and in vitro screening for antitubercular and antifungal activity shown that azolo cinnoline analogs will be safe, fast acting, less toxic and potent antitubercular and antifungal agents. The azolo cinnoline analogs synthesised through molecular modelling studies will potentiate the target oriented attack on the microorganisms without affecting the normal tissues and these molecules can be utilised as potent antitubercular and antifungal drug candidate

Synthesis and in vitro biological evaluation of 2,3-substituted quinoline derivatives

Thesis (MSc)--Rhodes University, Science Faculty, Department of Chemistry, 202